22689 research outputs found
Sort by
Ribosome collisions trigger two distinct rescue pathways in E. coli
Get PDFDuring the translation elongation, ribosomes can encounter problems that cause them to stall. Ribosome rescue pathways recycle the stalled ribosome and target the mRNA and nascent
peptide for degradation. In bacteria, it remains unclear how rescue pathways distinguish ribosomes stalled in the middle of a transcript from actively translating ribosomes. In Chapter 2, we discovered the endonuclease SmrB In a genetic screen for novel rescue factors in E. coli. We found that SmrB cleaves mRNAs upstream of stalled ribosomes, allowing the ribosome rescue factor tmRNA (which acts on truncated mRNAs) to rescue upstream ribosomes. We also showed that SmrB binds collided ribosomes, which stimulates its cleavage activity. These findings reveal the underlying mechanism by which ribosome collisions trigger ribosome rescue in bacteria. Surprisingly, however, loss of SmrB and tmRNA does not lead to robust sensitivity of cells to antibiotics that inhibit elongation and cause collisions, suggesting the existence of additional, uncharacterized rescue mechanisms. In Chapter 3, we identify the DExH-box helicase HrpA as a second ribosome rescue factor in E. coli. HrpA rescues stalled ribosomes by splitting them into subunits in an mRNA dependent manner. This activity is selective for collided ribosomes and requires ATP hydrolysis. The cryo-EM structure of HrpA bound to collided ribosomes reveals that HrpA senses collisions by binding both the stalled and collided ribosome. Its helicase module binds mRNA downstream of the stalled ribosomes, where it likely exerts a pulling force to split the stalled ribosome. Loss of HrpA activity results in antibiotic sensitivity. These studies highlight the importance of ribosome splitting as a highly conserved ribosome rescue mechanism across all three domains of life and identify an important pathway in proteobacteria that allows them to tolerate ribosome-targeting antibiotics
MIXED METHODS EVALUATION OF SAFE STREETS BALTIMORE TO REDUCE COMMUNITY GUN VIOLENCE
No full textObjectives: Gun violence remains a significant public health crisis in the United States, disproportionately impacting Black youth from disinvested neighborhoods. Community Violence Interventions (CVI) such as Safe Streets aim to reduce gun violence through a public health approach of conflict mediation, behavior change, and community norm change. While non-carceral approaches to gun violence are crucial, CVI programs including Safe Streets have demonstrated mixed effectiveness. This dissertation evaluates the effectiveness of Safe Streets in reducing homicides and nonfatal shootings (NFS) among youth ages 15-24 in Baltimore City and explores Safe Streets workers' perceptions of neighborhood-level and organizational-level factors influencing program effectiveness and implementation.
Methods: Quantitatively, augmented synthetic control models assessed the impact of Safe Streets on youth homicides and NFS from 2007 to 2023. Qualitatively, semi-structured interviews with 27 Safe Streets workers across ten sites were conducted from July to November 2023. Interviews were transcribed and analyzed using a thematic constant comparative approach and integrated with the estimates of program impacts.
Results: Safe Streets was associated with statistically significant declines in youth homicides in six of the 11 sites and youth NFS in two sites. The program was also associated with statistically significant increases in youth homicides in one site and in youth NFS in two sites. Qualitative analysis identified differences in neighborhood dynamics, types of conflicts, community norm changes, the depth of community relationships, and policing across sites. Organizational challenges highlighted included conflicts between nonprofit and street timelines, instrumental support for staff, media impacts on staff morale, and challenges with an aging workforce.
Conclusions: Safe Streets has significantly reduced gun violence among youth in certain neighborhoods, but differences in neighborhood context across sites suggest that it may be more difficult for the program to be successful in some areas, and variability in community partnerships and descriptions of community norm change suggest mixed model fidelity at the community level. Difficulties in integrating nontraditional violence mediation work into large nonprofit management structures has increased challenges in program implementation. Future research investigating mechanisms of community norm change and community perceptions of the program, as well as innovations in media communications strategies, are needed
The Role of B Cells and Autoantibody Production in Atherosclerotic Cardiovascular Disease
No full textUnderstanding the formation of atherosclerotic plaques is a dire concern to human health and mitigating its impact is a large focus of cardiovascular research. These plaques form within the major arteries, occluding the flow of blood, and putting individuals at risk for major life-altering and life-threatening events. Arterial plaques are primarily composed of lipid-rich cellular deposits and emerge due to a failure of the routine immune system to foster proper clearance of lipids and debris. Recently, the role of the humoral immune system in plaque development has become better appreciated, with systemic antibody responses having both positive and negative implications for disease progression. These studies however did not determine the antigenic target of these antibodies. The work presented here answers this question to better determine the role and clinical potential of antibodies in cardiovascular disease.
Over the course of this investigation, the repertoires of germinal center (GC) B cells from atherosclerotic ApoE-/- mice and IgD-CD38+ activated B cells from humans were analyzed. Heavy mutation of their V-gene segments was observed, suggesting antibody selection. B cell receptors were cloned from single cell isolates and antigen identification showed reactivity to various self-proteins. Many of these proteins are expressed within the diseased tissue. Serum antibody ELISA measurements highlighted 7 antigens with consistent antibody responses in multiple ApoE-/- mice. In humans, 5 antigens were identified that correlated with Framingham risk scores in males. Further study of two of these human antigens showed decades-long persistent antibody responses, suggesting individuals can become immunologically predisposed to cardiovascular disease. Furthermore, immunization with these antigens resulted in increased plaque burden in ApoE-/- mice, illustrating the potential for autoantibodies to promote plaque development. Together, this work identifies the production of autoreactive antibodies as a key target for understanding the development of cardiovascular disease
Chemical Stabilization of Novel Inorganic Quantum Materials
No full textIn the development of novel quantum materials, rational design is often complicated by the limited overlap between phase stability and bulk synthetic capability. While traditional solid state synthesis techniques have long determined what can be made and are constantly improving and expanding, they also present limitations. In this dissertation, I provide several examples of the leveraging of chemical intuition through less conventional and adapted synthesis techniques to stabilize and improve upon a variety of quantum materials, ranging from semiconductors to frustrated magnets, and spanning a wide variety of common and novel lattice geometries.
In Chapter 1, I begin with an evaluation of the origins of magnetism, magnetic order, and magnetic frustration in the context of the current frontiers in the search for a true quantum spin liquid state in a real material. In Chapter 2, I introduce several conventional and relatively underexplored synthesis methods utilized in the course of this work, as well as unconventional adaptations thereof. Chapter 3 shows the use of a complex Sc-Zr-I gas phase intermediate in the chemical vapor transport of a novel visible light band gap semiconductor, ScSI, a missing member of the RESI family of materials. Chapter 4 highlights the often complex balance of hydrothermal reaction conditions that is necessary to stabilize novel phases, particularly in the case of corkite, PbFe3(PO4)(SO4)(OH)6, a jarosite-family kagom\'e antiferromagnet (AFM). Chapter 5 shows an example of the chemical tuning of honeycomb AFM BaCo2(AsO4)2 through a critical point via partial arsenic substitution with vanadium. In Chapter 6, I show how the use of uncommon and mixed mineralizer species in the course of hydrothermal syntheses can be used to lower the energetic barrier to phase stabilization and tune magnetic ground states, as in the case of distorted honeycomb AFM Co2Te3O8. Finally, Chapter 7 illustrates how the expanded synthetic flexibility afforded by hydroflux methods can be used in the stabilization of a wide variety of novel magnetic materials, here in the case of zemannite-type K7Co6Te11O46H29+delta and its analogues
Oral History Interview with Bernard Lo
No full textThis interview was conducted remotely as part of Moral Histories: Voices and Stories from the Founding Figures of Bioethics, an oral history project of the Johns Hopkins Berman Institute of Bioethics. Dr. Bernard Lo is Professor of Medicine Emeritus and Director Emeritus of the Program in Medical Ethics at the University of California, San Francisco (UCSF). He is also President Emeritus of the Greenwall Foundation in New York, New York. He is the author of Resolving Ethical Dilemmas: A Guide for Clinicians (5th ed., 2014) and of Ethical Issues in Clinical Research (2010). Dr. Lo’s areas of expertise include ethical issues concerning decision-making near the end-of-life, stem cell research, oversight of human participants research, the doctor-patient relationship, and conflicts of interest.
Dr. Lo discusses his Chinese immigrant upbringing in Philadelphia, his transition from physics to medicine, and how his career in clinical medical ethics began, a time when he managed one critically ill patient's end-of-life care and another bone marrow transplant case. He discusses the early days and long-term impact of HIV AIDS on medical ethics and his own work with HIV patients, emphasizing the ethical challenges faced during the AIDS epidemic, including fears among healthcare workers and the need for safer practices. Dr. Lo describes the creation of the medical ethics program at UCSF, including challenges and successes in building infrastructure and relationships. The conversation also touches on the influence of the West Coast culture on his work and personal life, including family dynamics and the importance of diversity. He discusses the ethical guidelines for stem cell research at UCSF and his role in the California Institute for Regenerative Medicine (CIRM), including regulations for gamete donor consent and compensation for research-related harms. Lo highlights the many ethical considerations that arose during the Covid-19 pandemic, particularly resource allocation and vaccine hesitancy. He ends by describing the community-building work he fostered among early-career bioethicists, the importance of mentorship, and the impact of ethics textbooks on medical education
UNPACKING THE PAST: A PERSONAL HISTORY OF SCIENCE
No full textThe essays and articles in this collection cover topics ranging from environmental issues and nature to space exploration, dissections, and the Dewey Decimal System. The collection addresses these wide-ranging topics through a historical lens and is primarily concerned with the following question: How does the past shape the present? More specifically, how does the history of science shape what we know today, and how do our personal histories influence the way we interact with the body of scientific knowledge
COMPARATIVE ANALYSIS OF GREEN AND PINK HYDROGEN PRODUCTION IN JAPAN BASED ON A PAPTIAL CIRCULAR ECONOMY APPROACH
Get PDFGiven Japan's energy and environmental situations, this research study seeks to explore the best reasonable, practical, and economic future (2040-beyond) source of clean hydrogen (green or pink) for Japan if produced based on a partial circular economy approach. The paper explains the capstone's background and rationale, Japanese energy and environmental security, resilience and reliability situations, types of hydrogen production, and the current state of clean hydrogen development in Japan. The analysis in this research paper builds upon the inspiration of the Japanese mottainai movement and three theoretical frameworks governing the selection of data and criteria for comparative analysis of green and pink hydrogen production in Japan based on a partial circular economy approach. First, the study uses the technical cycle of the Ellen MacArthur Foundation's (2024) circular economy system diagram for structuring comparative analysis. The author's previously developed qualitative concepts, such as the quasi-revolutionary transition for developing US coastal green H2 hubs and nexus-integrated policies for Japan, also inform the paper's methodology. The study also addresses limitations and provides future research directions
OVERCOMING CHALLENGES: ENHANCING RESIDENTIAL HEAT PUMP WATER HEATER ADOPTION IN THE SOUTHEAST U.S. WITH BEHAVIORAL SCIENCE ELEMENTS
Get PDFThe residential sector in the Southeastern United States represents a key opportunity for decarbonization, given its high electricity use for water heating and the prevalence of inefficient electric resistance water heaters. Heat pump water heaters (HPWHs) are a promising alternative, offering 2-3 times greater efficiency, but their adoption remains low due to supply chain bottlenecks, high upfront costs, and consumer hesitancy. This paper integrates behavioral science into public policy to address these barriers, leveraging proven mechanisms such as challenges, commitments, and the principle of making it easy. By targeting specific supply chain actors—manufacturers, retailers, and installers—behavioral approaches can transform the HPWH market. Recommendations include incentivizing commitments from manufacturers to stabilize supply, initiating retailer challenges to drive competition and visibility, and reducing barriers for installers through streamlined training and education. These strategies aim to improve HPWH adoption, reduce emissions, and provide cost savings for households, ultimately contributing to a decarbonized residential sector in the Southeas
Identifying Challenges and Policy Priorities for Climate Mitigation in Emerging Market Economies
Get PDFThe global emissions landscape has changed significantly with the rise of middle-income or emerging market economies (EMEs). Rapid industrialization and growing roles in global trade have positioned EMEs like China, India, Saudi Arabia, and Indonesia among the world’s largest greenhouse gas emitters. Their growing energy consumption and reliance on fossil fuels distinguish them from other non-Annex I developing countries under the UNFCCC. Despite making voluntary climate pledges under the Paris Agreement, EMEs face challenges in balancing economic development with meaningful climate action. This study explores the contexts, energy profiles, and mitigation challenges of four major EME emitters. Drawing on national reports submitted to the UNFCCC, we identify shared characteristics, including prioritization of economic development, energy security challenges, and insufficient climate pledges. The findings emphasize the need for tailored strategies, with a focus on technological innovation and transitional finance from the international community, to support EMEs in achieving their climate goals
EVALUATING THE READINESS OF AMERICAN GAS UTILITIES FOR HYDROGEN BLENDING
Get PDFThis study evaluated the readiness of American Gas Utilities for hydrogen blending, with a focus on the top 30 gas utilities according to the overall customers. Hydrogen blending is the process of mixing natural gas with hydrogen gas at varying concentrations which can reduce carbon emissions to help reach long-term decarbonization goals. The research focused on identifying each utility's current state of readiness and providing recommendations and opportunities for utilities to enhance their readiness for hydrogen blending. The study focused on infrastructure compatibility, regulatory compliance, technical expertise, hydrogen supply, economic viability, community engagement, and the overall environmental impact to determine how prepared a utility is for a future of hydrogen blending. The study concluded that 20 utilities have low readiness, and 10 utilities have moderate readiness for hydrogen blending