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NPJ Vaccines Jun 2024Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit...
Gammaherpesviruses are oncogenic viruses that establish lifelong infections and are significant causes of morbidity and mortality. Vaccine strategies to limit gammaherpesvirus infection and disease are in development, but there are no FDA-approved vaccines for Epstein-Barr or Kaposi sarcoma herpesvirus. As a new approach to gammaherpesvirus vaccination, we developed and tested a replication-deficient virus (RDV) platform, using murine gammaherpesvirus 68 (MHV68), a well-established mouse model for gammaherpesvirus pathogenesis studies and preclinical therapeutic evaluations. We employed codon-shuffling-based complementation to generate revertant-free RDV lacking expression of the essential replication and transactivator protein encoded by ORF50 to arrest viral gene expression early after de novo infection. Inoculation with RDV-50.stop exposes the host to intact virion particles and leads to limited lytic gene expression in infected cells yet does not produce additional infectious particles. Prime-boost vaccination of mice with RDV-50.stop elicited virus-specific neutralizing antibody and effector T cell responses in the lung and spleen. In contrast to vaccination with heat-inactivated WT MHV68, vaccination with RDV-50.stop resulted in a near complete abolishment of virus replication in the lung 7 days post-challenge and reduction of latency establishment in the spleen 16 days post-challenge with WT MHV68. Ifnar1 mice, which lack the type I interferon receptor, exhibit severe disease and high mortality upon infection with WT MHV68. RDV-50.stop vaccination of Ifnar1 mice prevented wasting and mortality upon challenge with WT MHV68. These results demonstrate that prime-boost vaccination with a gammaherpesvirus that is unable to undergo lytic replication offers protection against acute replication, impairs the establishment of latency, and prevents severe disease upon the WT virus challenge. Our study also reveals that the ability of a gammaherpesvirus to persist in vivo despite potent pre-existing immunity is an obstacle to obtaining sterilizing immunity.
PubMed: 38914546
DOI: 10.1038/s41541-024-00908-x -
Scientific Data Jun 2024We present 4k video and whole transcriptome data for seven deep-sea invertebrate animals collected in the Eastern Pacific Ocean during a research expedition onboard the...
We present 4k video and whole transcriptome data for seven deep-sea invertebrate animals collected in the Eastern Pacific Ocean during a research expedition onboard the Schmidt Ocean Institute's R/V Falkor in August of 2021. The animals include one jellyfish (Atolla sp.), three siphonophores (Apolemia sp., Praya sp., and Halistemma sp.), one larvacean (Bathochordaeus mcnutti), one tunicate (Pyrosomatidae sp.), and one ctenophore (Lampocteis sp.). Four of the animals were sequenced with long-read RNA sequencing technology, such that the reads themselves define a reference assembly for those animals. The larvacean tissues were successfully preserved in situ and has paired long-read reference data and short read quantitative transcriptomic data for within-specimen analyses of gene expression. Additionally, for three animals we provide quantitative image data, and a 3D model for one siphonophore. The paired image and transcriptomic data can be used for species identification, species description, and reference genetic data for these deep-sea animals.
Topics: Animals; Transcriptome; Invertebrates; Pacific Ocean; Aquatic Organisms; Sequence Analysis, RNA
PubMed: 38914539
DOI: 10.1038/s41597-024-03533-4 -
The Lancet. Global Health Jun 2024Pulse oximeters are essential for assessing blood oxygen levels in emergency departments, operating theatres, and hospital wards. However, although the role of pulse... (Review)
Review
Pulse oximeters are essential for assessing blood oxygen levels in emergency departments, operating theatres, and hospital wards. However, although the role of pulse oximeters in detecting hypoxaemia and guiding oxygen therapy is widely recognised, their role in primary care settings is less clear. In this Viewpoint, we argue that pulse oximeters have a crucial role in risk-stratification in both hospital and primary care or outpatient settings. Our reanalysis of hospital and primary care data from diverse low-income and middle-income settings shows elevated risk of death for children with moderate hypoxaemia (ie, peripheral oxygen saturations [SpO] 90-93%) and severe hypoxaemia (ie, SpO <90%). We suggest that moderate hypoxaemia in the primary care setting should prompt careful clinical re-assessment, consideration of referral, and close follow-up. We provide practical guidance to better support front-line health-care workers to use pulse oximetry, including rethinking traditional binary SpO thresholds and promoting a more nuanced approach to identification and emergency treatment of the severely ill child.
PubMed: 38914087
DOI: 10.1016/S2214-109X(24)00209-2 -
JMIR MHealth and UHealth Jun 2024Conversational chatbots are an emerging digital intervention for smoking cessation. No studies have reported on the entire development process of a cessation chatbot.
BACKGROUND
Conversational chatbots are an emerging digital intervention for smoking cessation. No studies have reported on the entire development process of a cessation chatbot.
OBJECTIVE
To describe the user-centered design development process for a novel and comprehensive quit smoking conversational chatbot called "QuitBot."
METHODS
The four years of formative research for developing QuitBot followed an eleven-step process: (1) specifying a conceptual model, (2) conducting content analysis of existing interventions (63 hours of intervention transcripts), (3) assessing user needs, (4) developing the chat's persona ("personality"), (5) prototyping content and persona, (6) developing full functionality, (7) programming the QuitBot, (8) conducting a diary study, (9) conducting a pilot randomized trial, (10) reviewing results of the trial, and (11) adding a free-form question and answer (QnA) function, based on user feedback from pilot trial results. The process of adding a QnA function itself involved a three-step process: (a) generating QnA pairs, (b) fine tuning Large Language Models (LLMs) on QnA pairs, and (c) evaluating the LLM model outputs.
RESULTS
A quit smoking program spanning 42 days of 2 to 3-minute conversations covering topics ranging from motivations to quit, setting a quit date, choosing FDA-approved cessation medications, coping with triggers, and recovering from lapses/relapses. In a pilot randomized trial with 96% three-month outcome data retention, QuitBot demonstrated high user engagement and promising cessation rates compared to the National Cancer Institute's SmokefreeTXT (SFT) text messaging program-particularly among those who viewed all 42 days of program content: 30-day complete-case, point prevalence abstinence (PPA) rates at three-month follow-up were 63% (39/62) for QuitBot vs. 38% (45/117) for SFT (OR = 2.58; 95% CI: 1.34, 4.99; P =.005). However, Facebook Messenger (FM) intermittently blocked participants' access to QuitBot so we transitioned from FM to a standalone smartphone app as the communication channel. Participants' frustration with QuitBot's inability to answer their open-ended questions lead to us develop a core conversational feature enabling users to ask open-ended questions about quitting cigarette smoking and for the QuitBot to respond with accurate and professional answers. To support this functionality, we developed a library of 11,000 QnA pairs on topics associated with quitting cigarette smoking. Model testing results showed that Microsoft's Azure-based QnA maker effectively handled questions that matched our library of 11,000 QnA pairs. A fine-tuned, contextualized GPT3.5 responds to questions that are not within our library of QnA pairs.
CONCLUSIONS
The development process yielded the first LLM-based quit smoking program delivered as a conversational chatbot. Iterative testing led to significant enhancements, including improvements to the delivery channel. A pivotal addition was the inclusion of a core LLM-supported conversational feature allowing users to ask open-ended questions.
CLINICALTRIAL
ClinicalTrials.gov Identifier, NCT03585231.
PubMed: 38913882
DOI: 10.2196/57318 -
ELife Jun 2024Metabolic disorders are highly prevalent in modern society. Exercise mimetics are defined as pharmacological compounds that can produce the beneficial effects of...
Metabolic disorders are highly prevalent in modern society. Exercise mimetics are defined as pharmacological compounds that can produce the beneficial effects of fitness. Recently, there has been increased interest in the role of eugenol and transient receptor potential vanilloid 1 (TRPV1) in improving metabolic health. The aim of this study was to investigate whether eugenol acts as an exercise mimetic by activating TRPV1. Here, we showed that eugenol improved endurance capacity, caused the conversion of fast-to-slow muscle fibers, and promoted white fat browning and lipolysis in mice. Mechanistically, eugenol promoted muscle fiber-type transformation by activating TRPV1-mediated CaN signaling pathway. Subsequently, we identified IL-15 as a myokine that is regulated by the CaN/nuclear factor of activated T cells cytoplasmic 1 (NFATc1) signaling pathway. Moreover, we found that TRPV1-mediated CaN/NFATc1 signaling, activated by eugenol, controlled IL-15 levels in C2C12 myotubes. Our results suggest that eugenol may act as an exercise mimetic to improve metabolic health via activating the TRPV1-mediated CaN signaling pathway.
Topics: TRPV Cation Channels; Animals; Interleukin-15; Eugenol; Mice; Muscle Fibers, Skeletal; NFATC Transcription Factors; Physical Conditioning, Animal; Signal Transduction; Male; Mice, Inbred C57BL; Myokines
PubMed: 38913071
DOI: 10.7554/eLife.90724 -
Journal of Applied Biomedicine Jun 2024Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl...
Diffuse large B-cell lymphoma (DLBCL) stands out as the most common type of malignant cancer, representing the majority of cases of non-Hodgkin's lymphoma. Ethyl pyruvate (EP) is a derivative of pyruvic acid and found to have potent anti-tumor properties. Despite its potential benefits, the impact of EP on DLBCL remains ambiguous. Our objective is to elucidate the role of EP in modulating the development of DLBCL. Analysis of cholecystokinin-8 (CCK-8) revealed that treatment with EP significantly diminished the viability of DLBCL cells. Furthermore, EP administration suppressed colony formation and hindered cell adhesion and invasion in DLBCL cells. Examination of cell cycle progression showed that EP treatment induced arrest at the G1 phase and subsequently reduced the S phase population in DLBCL cells. EP treatment consistently exhibited apoptosis-inducing properties in Annexin-V assays, and notably downregulated the expression of Bcl-2 while increasing levels of proapoptotic cleaved caspase 3 and BAX in DLBCL cells. Additionally, EP treatment decreased the overexpression of c-Jun in c-Jun-transfected DLBCL cells. Further, EP demonstrated DNA-damaging effects in TUNEL assays. In vivo, xenograft animal models revealed that EP treatment significantly mitigated DLBCL tumor growth and suppressed DLBCL cell adhesion to bone marrow stromal cells. In summary, these findings suggest that EP mitigates DLBCL progression by inducing apoptosis, inducing cell cycle arrest, and promoting DNA damage.
Topics: Pyruvates; Lymphoma, Large B-Cell, Diffuse; Humans; Animals; Cell Adhesion; Cell Proliferation; Cell Line, Tumor; Mice; Apoptosis; Proto-Oncogene Proteins c-jun; Xenograft Model Antitumor Assays
PubMed: 38912866
DOI: 10.32725/jab.2024.014 -
JCI Insight May 2024Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection...
Identifying immune correlates of protection is a major challenge in AIDS vaccine development. Anti-Envelope antibodies have been considered critical for protection against SIV/HIV (SHIV) acquisition. Here, we evaluated the efficacy of an SHIV vaccine against SIVmac251 challenge, where the role of antibody was excluded, as there was no cross-reactivity between SIV and SHIV envelope antibodies. After 8 low-dose intrarectal challenges with SIVmac251, 12 SHIV-vaccinated animals demonstrated efficacy, compared with 6 naive controls, suggesting protection was achieved in the absence of anti-envelope antibodies. Interestingly, CD8+ T cells (and some NK cells) were not essential for preventing viral acquisition, as none of the CD8-depleted macaques were infected by SIVmac251 challenges. Initial investigation of protective innate immunity revealed that protected animals had elevated pathways related to platelet aggregation/activation and reduced pathways related to interferon and responses to virus. Moreover, higher expression of platelet factor 4 on circulating platelet-leukocyte aggregates was associated with reduced viral acquisition. Our data highlighted the importance of innate immunity, identified mechanisms, and may provide opportunities for novel HIV vaccines or therapeutic strategy development.
Topics: Animals; Simian Acquired Immunodeficiency Syndrome; Simian Immunodeficiency Virus; SAIDS Vaccines; Macaca mulatta; Immunity, Innate; CD8-Positive T-Lymphocytes; Antibodies, Viral; Male; Vaccines, Attenuated
PubMed: 38912579
DOI: 10.1172/jci.insight.175800 -
Heliyon Jun 2024Alzheimer's disease (AD) is a brain illness that causes cognitive impairment in the elderly, especially females, as a result of genetics, hormones, and life experiences....
Alzheimer's disease (AD) is a brain illness that causes cognitive impairment in the elderly, especially females, as a result of genetics, hormones, and life experiences. It becomes more severe with age and is associated with cardiovascular disease, hypertension, and diabetes. Beta-amyloid plaques and hyper phosphorylated Tau protein buildup are common clinical findings. Misfiling of amyloid precursor protein (APP) and Amyloid beta peptide (Aβ) proteins contributes to Alzheimer's disease. Enzyme Acetylcholinesterase enzyme interacts with amyloid-beta, enhancing its accumulation in insoluble plaques, leading to successful treatment for Alzheimer's disease primarily based on lowering this enzyme. Treatments include using the Rivastigmine for mild, moderate, or severe Alzheimer's disease, which inhibits acetylcholinesterase, but may cause side effects; Solanine derivatives, nightshade toxin, it is cholinesterase inhibitory, may mitigate Alzheimer's illness is progressing. In this research utilized a molecular docking program, which is a computer's computational ability to determine the optimal position for a specific compound to bind to a protein or target, forming a target-ligand complex and displaying biological activity and aiding in the development of effective anti-AD treatments and understanding AD pathological mechanisms. The study examined complexes of 3LII (Acetylcholinesterase receptor) in the A and B chain with Solanine and Rivastigmine derivatives, using an in-silico approach. PyRx default sorter was used to improve docking accuracy. Four compounds were selected based on their higher binding affinities in chain A and B. The results showed that Solanine derivatives (alpha-Solanine, Beta1-Solanine and Beta2-Solanine) have higher binding strength (-9.0,-9.3 and -8.6) than Rivastigmine (-7.2) in chain A, and also the binding strength was high for the Solanine derivatives (alpha-Solanine, Beta1-Solanine, and Beta2-Solanine) (-9.0,-8.8 and -8.9) is higher than Rivastigmine (-6.0) in the chain B. Solanine derivatives showed higher binding strength with acetylcholinesterase, potentially for to reduce the progression of the disease.
PubMed: 38912489
DOI: 10.1016/j.heliyon.2024.e32209 -
Heliyon Jun 2024In recent years, the use of solar photovoltaic (PV) energy, which is one of the leading renewable energy sources, has become increasingly widespread around the world due...
In recent years, the use of solar photovoltaic (PV) energy, which is one of the leading renewable energy sources, has become increasingly widespread around the world due to its numerous advantages. However, PV-based electricity generation necessitates a large amount of land. Agrivoltaic (AV) systems, an innovative approach to combining agricultural and electricity production in the same area through solar modules positioned several meters above the surface of the ground, are growing rapidly in renewable energy and farming communities. This study explores Turkey's solar power generation and agricultural activities, combining crop cultivation and electricity generation for sustainable development on the same land. Furthermore, the AV potential for the most agriculture ten cities in different climate zones in Turkey is investigated using the PVsyst program. A list of the most commonly grown crops in the ten selected cities and the types of AV systems that can be employed with these crops is provided. The results show that AV systems present a great opportunity for the optimal integration of solar power generation with food production, especially for the cities of Konya, Kayseri, and Manisa, with the most ideal conditions for agricultural and solar power production. By combining the solar power potential of the country with the production capacity of arable lands, the increasing energy needs can be met and more efficient agricultural production can be provided. This study is expected to demonstrate that in specific regions of Turkey, AV farming will be suitable for certain crops.
PubMed: 38912471
DOI: 10.1016/j.heliyon.2024.e32300 -
Perspectives on Medical Education 2024Medical education has acknowledged the impact of structural societal factors on health, prompting the need for curricula seeking to eliminate health inequities upstream...
PROBLEM & BACKGROUND
Medical education has acknowledged the impact of structural societal factors on health, prompting the need for curricula seeking to eliminate health inequities upstream while simultaneously caring for downstream effects of existing inequities. The Keck School of Medicine of USC (KSOM) implemented one such comprehensive curriculum, Health Justice and Systems of Care (HJSC), integrating health systems science, structural competency, and service-learning in a required course spanning the pre-clerkship and clerkship phases with an optional post clerkship elective.
APPROACH
The HJSC course addresses topics including racism in medicine, health inequities, and health systems science. Using transformative learning theory, it fosters critical consciousness and structural competency. Assessments include case analyses, reflections, team-based learning sessions, and group projects related to social justice in healthcare. The program aims to instill cultural humility and practical application, fostering a holistic approach to medical education that implores physicians to become advocates for health justice.
OUTCOMES OF THE INNOVATION
Feedback from students indicated generally positive perceptions of the curriculum. Students provided overall positive comments about discussions with guest speakers. However, students expressed a desire for more concrete examples of how health inequities can be remedied. Some found small-group activities less engaging. Other challenges included providing students of different readiness levels with tailored experiences and seamlessly integrating HJSC content within basic and clinical sciences courses.
CRITICAL REFLECTION
Next steps include continuing to integrate content into the science curriculum and clerkships, improving opportunities for meaningful student interactions, and enhancing faculty development to address health justice concerns in clinical settings.
Topics: Humans; Curriculum; Social Justice; Students, Medical; Delivery of Health Care; Clinical Clerkship
PubMed: 38912167
DOI: 10.5334/pme.1325