22689 research outputs found
Sort by
PLASTICIZERS AND NICASTRIN LOSS IN THE PATHOGENESIS OF THE INFLAMMATORY SKIN DISEASE HIDRADENITIS SUPPURATIVA
No full textHidradenitis Suppurativa (HS) is an inflammatory skin disorder with poorly understood etiology and few FDA approved treatments. Mutations in the gamma secretase (GS) membrane protease, particularly the Nicastrin (NCSTN) subunit, characterize hereditary HS, but the pathophysiology of the more common acquired HS is unclear, despite associations with smoking, obesity, and a diet containing ultra-processed foods (UPFs). Consistent with the hypothesis that the phenotypic overlap between acquired and hereditary HS suggests a shared dysfunction of NCSTN, we demonstrate that NCSTN protein is selectively lost in HS dermal fibroblasts but not keratinocytes to prime them for inflammation. We further hypothesized that the dramatic increase in incidence of acquired HS and its hormonal associations suggest Endocrine Disruptor (ED) chemicals as an environmental cause. Specifically, given the prevalence of plasticizer bisphenols and phthalates (p-EDs) in UPFs, we tested for their presence in HS skin and impact on NCSTN. p-EDs are elevated in the skin of HS patients but not controls, and even persist in ex-vivo cultured HS fibroblasts but not controls. p-EDs inhibit NCSTN protein expression at nanomolar concentrations in fibroblasts but not keratinocytes, and prime for inflammation as seen in NCSTN siRNA and HS fibroblasts. These results suggest how industrialization of the food supply can lead to disease and the importance of further focus on p-EDs to prevent HS and possibly other GS related diseases
DEEP LEARNING FOR OFF-TARGET EDITING PREDICTION
No full textThe CRISPR-Cas9 system provides the ability to apply targeted genomic alterations, but accuracy is pertinent to establishing safety. In addition to quantifying on-target editing rates, measuring off-target activity across the genome is important.
Cas9 cleaves the genome at a location specified by a guide RNA and imperfect complementarity can lead to cleavage that induces off-target editing. There are multiple cellular and biochemical methods used to measure off-target activity by marking the location of induced double stranded breaks or enriching cleaved sites. CHANGE-seq, a biochemical tagmentation method, measures the activity of Cas9 and is scalable. The authors and creators of CHANGE-seq published a study containing 201,934 off-target sites for 110 guide RNAs across 13 loci. While CHANGE-seq is scalable and less difficult than other methods, identifying all active off-target sites can prove to be laborious, especially independent of homology and with decreasing complementarity. In silico predictive models can aid in predicting higher risk guide RNAs to prioritize which guides should be further validated using cellular or biochemical methods.
Using data from the CHANGE-seq study and supplementing it with additional alignments across the genome, we trained a deep learning model that achieves an AUPRC of 0.72 with a baseline prevalence of 0.004 and validated the trained deep learning model on external data containing mismatches from non-CHANGE-seq assay sources. Through this external validation, the trained deep learning model outperformed other published predictive models like CRISPR-Net and demonstrated that the application of the model is not assay specific. To continue this work, further validation can be done to evaluate the performance of the trained deep model on data including indels. Ultimately, this trained deep learning model can be used to enrich for off-target sites and prioritize riskier sites that are more likely to be active off-target sites
Single Crystal Metal–Organic Framework Field–Effect Nanosensors
Get PDFThe inevitable and accelerating miniaturization of electronics requires new solutions to accommodate sleeker form factors without compromising on computational or processing efficiency. While fabrication strategies have been developed on current semiconductor materials to decrease process node size, as we approach the limit of device dimensions achievable by direct patterning, research has reoriented toward finding new semiconducting materials to integrate into computational device architectures. Nanomaterials offer novel optoelectronic and electrical properties that can be harnessed for multifunctional, high density device arrays. Nanomaterials, or low-dimensional materials whose dimensions are restricted to ~1–100 nm, offer an unprecedented degree of compositional, morphological, and structural tunability with exceptional mechanical and intrinsic properties. Integration of these materials into devices, however, is nontrivial. Precise synthetic strategies are required to produce high yield, high quality single crystals that are mechanically and chemically robust against fabrication. Furthermore, a key requisite for synthesis is its industrial compatibility, that is, maintaining the material’s phase– and compositional–purity at scale. Even once single nanocrystals have been synthesized, their ability to withstand fabrication, i.e. lithography and removal of resist and metal films, is a significant barrier to entry in their commercial viability.
Metal–organic frameworks (MOFs) are an emerging class of nanomaterials whose intrinsically porous structure and long-range crystalline order have been long-exploited for passive applications in gas sequestration, storage, and separations. However, discrete nanocrystals of MOFs are rich with opportunities for the active components in electronic devices. Their porosity and crystallinity, coupled with rationally designed electronic and stimulus-responsive characteristics, provides a platform for next generation multi-functional devices. However, exploration of MOF electronics is bottlenecked by an incompatibility with lithographic methods typically used with all-inorganic atomic crystals at scale. This work presents the first MOF single nanocrystal field-effect transistor devices, and the development of industrially compatible synthetic and fabrication techniques for high yield prototyping. To demonstrate the efficacy and sensitivity of these devices, single crystal chemical sensors were fabricated and demonstrated ultra-low threshold gate-tunable phosphine sensing
ASSESSING COMPUTING RELIABILITY DESIGN PRACTICES FOR LOW-SWAP SPACECRAFT AVIONICS BY COMPARISON OF THE INGENUITY HELICOPTER AND DRAGONFLY MISSIONS
Get PDFAs mission science requirements increase in ambition, there has been increased discussion of identifying computing components with the performance and size, weight and power (SWaP) necessary to meet them. This ambition has resulted in increased tolerance of risk in component selection for avionics system design, with a focus on commercial, off-the-shelf (COTS) solutions for command and data handling (C&DH) systems. The potential of these higher-performance, lower-SWaP parts has been demonstrated in missions such as the Ingenuity Helicopter, a demonstration rotorcraft vehicle included in the Mars 2020 mission. An upcoming mission, Dragonfly, provides a control sample of engineering for traditional space flight computing with their science objective, exploration of the surface of Titan using a rotorcraft system. In comparing the computing reliability design of these two missions, we identify common design themes that each mission implemented, and discuss the scope of future work that should be pursued to make use of COTS low-SWaP solutions more commonplace in spacecraft avionics.
This paper begins by laying out causes of electronics failure and metrics used to measure computing system failure and reliability. Having established these, we discuss common ways in which computing system reliability is improved and graphical and mathematic methods commonly used to assess overall system reliability. This is followed by a discussion of standards maintained by NASA and the United States Military regarding acceptable mission risks, the levels of reliability and technological maturity expected, and electronic hardware and software standards.
The design teams behind Ingenuity and Dragonfly, NASA Jet Propulsion Lab and Johns Hopkins University - Applied Physics Lab, respectively, we argue, are institutions with enough similarities that we can isolate input parameters and design scopes in design decisions, and discount factors like lack of institutional knowledge, resources or experience. We set up areas of study for each program and then provide overviews of each mission, their hardware and software architectures, and identify computing reliability design strategies each mission employed. In the last section, we propose a path toward developing flight heritage for similar components, including application spaces with potential products that can be adapted and methods to improve reliability in these products
SERUM METABOLOMIC SIGNATURE OF THE MEDITERRANEAN-DASH INTERVENTION FOR NEURODEGENERATIVE DELAY (MIND) DIET
Get PDFAdherence to the Mediterranean-DASH Intervention for Neurodegenerative Delay (MIND) diet is associated with lower risk of dementia and cognitive decline. There is a lack of biomarkers of healthy dietary patterns, such as the MIND diet. With the advance of high-throughput technologies, metabolomics can be used to discover novel biomarkers as an objective method to reflect dietary consumption.
We aimed to investigate which serum metabolites are associated with adherence to the MIND diet and evaluate the metabolic impact of the MIND diet consumption.
In 3,908 Atherosclerosis Risk in Communities (ARIC) study participants, we calculated a modified MIND diet score based on a 66-item self-reported food frequency questionnaire (FFQ). We further examined associations between 360 untargeted serum metabolites and the MIND diet score using multivariable linear regression models in 2 subgroups of ARIC study participants. Results were meta-analyzed across the 2 subgroups using fixed effects regression to identify significant metabolites after Bonferroni correction. We examined associations between metabolites and food components of the MIND diet. C-statistics were calculated to evaluate the prediction of high adherence to the MIND diet score using significant metabolites beyond participant characteristics.
The mean age was 54 years; 60% were female, and 61% were black. We identified 27 metabolites that were significantly associated with the MIND diet score (lipids, n=13; amino acids, n=5; xenobiotics, n=3; cofactors and vitamins, n=3; carbohydrates n=2; nucleotide n=1). The top 4 metabolites that improved the prediction of high dietary adherence to the MIND diet were 7-methylxanthine, theobromine, docosahexaenoate (DHA), and 3-carboxy-4-methyl-5-propyl-2-furanpropanoate (CMPF).
In a US community-based study, 27 metabolomic markers were correlated with the MIND diet, which represent the metabolic impact of consuming the MIND diet. The biomarkers, if further validated, could be useful to objectively assess adherence to the MIND diet
The Political Ecosystem of Nuclear Energy in China: China as a Catalytic Developmental State
Get PDFChina is leading the global expansion of nuclear energy, which has become mainstream as many developed and developing countries adopt nuclear energy development policies to address growing energy security and climate change concerns. A common response to the question of what is driving the rapid expansion of China's nuclear capacity often attributes it to China's capacity to leverage state-controlled financing and supply chains. While such an empirical explanation is compelling, economic viability is not a sufficient condition for nuclear growth.
In this thesis, I argue that the involvement of local governments in the nuclear development project is the driving force behind China's nuclear expansion. In advancing this argument, I propose the concept of a "catalytic developmental state" to shed light on the political system of China's nuclear energy sector that has enabled the country to implement its ambitious nuclear development policy. Drawing upon and modifying the developmental state theory initially developed to capture economic transformation in East Asia, the framework of catalytic developmental state explains how the Chinese leadership's strategic decision to develop nuclear energy was translated into an engine of nuclear growth despite the fragmented bureaucracy and convoluted public-private relations. In a catalytic developmental state, when the state adopts a policy to develop a particular industry strategically, and its bureaucracy and enterprises attempt to implement it but are challenged by a variety of internal and external factors, catalytic actors step in to help achieve the policy goal.
Incorporating the active development of nuclear energy into a national strategy to enhance energy security in the wake of energy crisis in 2003-2005, China designed its institutions to incentivize and manage the diverse actors to ensure that conflicts of interest among them did not impede development; in particular, local governments have been encouraged to actively participate in nuclear projects by the so-called “travel pass (lutiao)” in China’s nuclear industry which allows the preliminary construction to begin prior to the formal approval by the State Council is granted. They have provided valuable support to the activities of state-owned enterprises and contributed to the expeditious implementation of nuclear projects. In return, local governments benefit from political promotion as well as increased revenues and local economic development when the nuclear project is successfully implemented.
A cross-national comparison employing the framework of catalytic developmental state highlights the salience of central-local relations in China, which play a critical role in nuclear development, while other major nuclear power states have struggled to implement their nuclear energy policies, in the case of the United States and Japan, or have taken a different path to focus on nuclear exports, in the case of Russia. The case studies of Liaoning and Hebei provinces demonstrate the importance of political leverage that local governments can use to pursue their energy development. The findings of the research add predictive power to the catalytic developmental state framework, allowing us to focus on the role of local governments in analyzing the uncertain future of China’s nuclear expansion
Oral History Interview with Lori Andrews
No full textThis interview with Lori Andrews is a part of “Moral Histories: Voice and Stories from the Founding Figures of Bioethics,” an oral history project of the Johns Hopkins Berman Institute of Bioethics. Lori Andrews is a Professor Emerita of Law at Chicago Kent College of Law. She is the author of a number of books, both non-fiction and fiction, including I Know Who You Are and I Saw What You Did: Social Networks and the Death of Privacy and Immunity. Professor Andrews is known for her expertise regarding privacy with regards to reproductive and genetic technologies. She has served as an advisor to such organizations as the March of Dimes, the World Health Organization, the National Institutes of Health, and the Centers for Disease Control and Prevention.
Andrews discusses growing up in the suburbs of Chicago and the formative experience of observing her sister’s interactions with the healthcare system. She reflects on important mentors, from her elementary school teacher who impressed upon her the importance of hands-on learning to graduate school mentors. She discusses her time at Yale Law School under the mentorship of Lowell Levin, where she began to combine public health studies with legal research projects. Andrews detailed her work on the legal and ethical implications of reproductive technologies, cloning, newborn screening laws, and medical errors, in which she advocated for informed consent and patient empowerment. She also highlighted her work on genetic testing and gene patents, particularly the landmark case against Myriad Genetics. Andrews criticized the increasing role of industry and private interests on bioethics committees, the hype around technological advancements, and the lack of regulation in reproductive technologies, particularly sperm banks. The interview ends with a broad discussion of privacy, including the impact of social media and the importance of interdisciplinary approaches in bioethics
Oral History Interview with George J. Annas
No full textThis interview with George J. Annas, JD, is 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. Prof. Annas is William Fairfield Warren Distinguished Professor at Boston University (BU), Director of the Center for Health Law, Ethics & Human Rights of the BU School of Public Health, and a professor in the BU School of Medicine and School of Law. He is the cofounder of Global Lawyers and Physicians, a transnational professional association of lawyers and physicians working together to promote human rights and health.
Prof. Annas recounts growing up in St. Cloud, Minnesota, discussing his Catholic upbringing and schooling before his eventual transfer from St. Thomas University to Harvard University and then Harvard Law School. Sharing his experiences in and following law school, Annas describes the process of appealing his two Vietnam War draft orders, becoming the first lawyer to receive an MPH at Harvard, and working as a Joseph P. Kennedy Foundation Fellow in Medical Ethics. He explores the legal and ethical complexities of end-of-life decisions—including living wills, physician-assisted suicide, organ transplants, and right-to-die laws. He discusses the origin and several editions of his book, The Rights of Patients, and recounts stories about writing regular features for prominent medical journals.
Other topics discussed include Annas’ work with the Nuremberg Code files; his involvement with the Human Genome Project and genetic privacy issues; and his bioethics-themed comedy stand-up shows and Shelley’s Brain, a play based on
the story of Barney Clark’s artificial heart. Throughout the interview, Annas reflects broadly on his focus in human-centric legal writing, and his collaborations with doctors and medical professionals. He ends by outlining the four characteristics of the health care system discussed in The Rights of Patients, explaining his self-identification as a health lawyer, and reflecting on the need for sustainability and environmental considerations in bioethics
Oral History Interview with Anita Allen
No full textThis interview with Anita Allen, JD, PhD, is 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. Professor Allen is the Henry R. Silverman Professor of Law and Professor of Philosophy at the University of Pennsylvania. She is the author of several books, including Unpopular Privacy: What Must We Hide and Uneasy Access: Privacy for Women in a Free Society. She served on President Barack Obama’s Commission for the Study of Bioethical Issues in 2010. Professor Allen’s expertise addresses both the philosophical and social justice aspects of privacy, particularly women’s reproductive rights and data privacy.
Professor Allen discusses her upbringing as an "army brat" in Fort Warden, Washington, and her family's move to Atlanta, including difficult experiences in segregated schools post-Brown v. Board. She recounts her education at New College of Florida and the University of Michigan, her early interest in philosophy, and her transition to Harvard Law School. Allen shares her professional journey, from corporate law to teaching, along with her time spent as a news commentator. She also discusses her time spent with the National Endowment for the Humanities and on the advisory committee for the Human Genome Project. Allen offers her perspective on women’s reproductive rights, the overturning of Roe v. Wade, surrogacy, adoption, and interracial relationships, and the role of privacy in these issues. Allen describes her experience as a Black woman in philosophy, law, and bioethics, and discusses her work on Black pain. She concludes the interview talking about the importance of mental health law in the realm of bioethics