Capturing Multicellular System Designs Using Synthetic Biology Open Language (SBOL)

8 Pág.Synthetic biology aims to develop novel biological systems and increase their reproducibility using engineering principles such as standardization and modularization. It is important that these systems can be represented and shared in a standard way to ensure they can be easily understood, reproduced, and utilized by other researchers. The Synthetic Biology Open Language (SBOL) is a data standard for sharing biological designs and information about their implementation and characterization. Previously, this standard has only been used to represent designs in systems where the same design is implemented in every cell; however, there is also much interest in multicellular systems, in which designs involve a mixture of different types of cells with differing genotype and phenotype. Here, we show how the SBOL standard can be used to represent multicellular systems, and, hence, how researchers can better share designs with the community and reliably document intended system functionality.This work was supported in part by NSF Expeditions in Computing Program Award No. 1522074 as part of the Living Computing Project and by the Defense Advanced Research Projects Agency under Contract No. W911NF-17-2-0098. The views, opinions, and/or findings expressed are of the author(s) and should not be interpreted as representing official views or policies of the Department of Defense or the U.S. Government. A.G.-M. was supported by the SynBio3D project of the UK Engineering and Physical Sciences Research Council (No.EP/R019002/1) and the European CSA on biological standardization BIOROBOOST (EU Grant No. 820699)Peer reviewe

Pore dynamics and asymmetric cargo loading in an encapsulin nanocompartment

Encapsulins are protein nanocompartments that house various cargo enzymes, including a family of decameric ferritin-like proteins. Here, we study a recombinant Haliangium ochraceum encapsulin:encapsulated ferritin complex using cryo–electron microscopy and hydrogen/deuterium exchange mass spectrometry to gain insight into the structural relationship between the encapsulin shell and its protein cargo. An asymmetric single-particle reconstruction reveals four encapsulated ferritin decamers in a tetrahedral arrangement within the encapsulin nanocompartment. This leads to a symmetry mismatch between the protein cargo and the icosahedral encapsulin shell. The encapsulated ferritin decamers are offset from the interior face of the encapsulin shell. Using hydrogen/deuterium exchange mass spectrometry, we observed the dynamic behavior of the major fivefold pore in the encapsulin shell and show the pore opening via the movement of the encapsulin A-domain. These data will accelerate efforts to engineer the encapsulation of heterologous cargo proteins and to alter the permeability of the encapsulin shell via pore modifications

Drug repurposing prediction for COVID-19 using probabilistic networks and crowdsourced curation

Severe acute respiratory syndrome coronavirus two (SARS-CoV-2), the virus responsible for the coronavirus disease 2019 (COVID-19) pandemic, represents an unprecedented global health challenge. Consequently, a large amount of research into the disease pathogenesis and potential treatments has been carried out in a short time frame. However, developing novel drugs is a costly and lengthy process, and is unlikely to deliver a timely treatment for the pandemic. Drug repurposing, by contrast, provides an attractive alternative, as existing drugs have already undergone many of the regulatory requirements. In this work we used a combination of network algorithms and human curation to search integrated knowledge graphs, identifying drug repurposing opportunities for COVID-19. We demonstrate the value of this approach, reporting on eight potential repurposing opportunities identified, and discuss how this approach could be incorporated into future studies

Convalescent plasma in patients admitted to hospital with COVID-19 (RECOVERY): a randomised controlled, open-label, platform trial

SummaryBackground Azithromycin has been proposed as a treatment for COVID-19 on the basis of its immunomodulatoryactions. We aimed to evaluate the safety and efficacy of azithromycin in patients admitted to hospital with COVID-19.Methods In this randomised, controlled, open-label, adaptive platform trial (Randomised Evaluation of COVID-19Therapy [RECOVERY]), several possible treatments were compared with usual care in patients admitted to hospitalwith COVID-19 in the UK. The trial is underway at 176 hospitals in the UK. Eligible and consenting patients wererandomly allocated to either usual standard of care alone or usual standard of care plus azithromycin 500 mg once perday by mouth or intravenously for 10 days or until discharge (or allocation to one of the other RECOVERY treatmentgroups). Patients were assigned via web-based simple (unstratified) randomisation with allocation concealment andwere twice as likely to be randomly assigned to usual care than to any of the active treatment groups. Participants andlocal study staff were not masked to the allocated treatment, but all others involved in the trial were masked to theoutcome data during the trial. The primary outcome was 28-day all-cause mortality, assessed in the intention-to-treatpopulation. The trial is registered with ISRCTN, 50189673, and ClinicalTrials.gov, NCT04381936.Findings Between April 7 and Nov 27, 2020, of 16 442 patients enrolled in the RECOVERY trial, 9433 (57%) wereeligible and 7763 were included in the assessment of azithromycin. The mean age of these study participants was65·3 years (SD 15·7) and approximately a third were women (2944 [38%] of 7763). 2582 patients were randomlyallocated to receive azithromycin and 5181 patients were randomly allocated to usual care alone. Overall,561 (22%) patients allocated to azithromycin and 1162 (22%) patients allocated to usual care died within 28 days(rate ratio 0·97, 95% CI 0·87–1·07; p=0·50). No significant difference was seen in duration of hospital stay (median10 days [IQR 5 to >28] vs 11 days [5 to >28]) or the proportion of patients discharged from hospital alive within 28 days(rate ratio 1·04, 95% CI 0·98–1·10; p=0·19). Among those not on invasive mechanical ventilation at baseline, nosignificant difference was seen in the proportion meeting the composite endpoint of invasive mechanical ventilationor death (risk ratio 0·95, 95% CI 0·87–1·03; p=0·24).Interpretation In patients admitted to hospital with COVID-19, azithromycin did not improve survival or otherprespecified clinical outcomes. Azithromycin use in patients admitted to hospital with COVID-19 should be restrictedto patients in whom there is a clear antimicrobial indication

Developing an innovative pediatric integrated mental health care program: interdisciplinary team successes and challenges.

INTRODUCTION: Children and adolescents often do not receive mental healthcare when they need it. By 2021, the complex impact of the COVID-19 pandemic, structural racism, inequality in access to healthcare, and a growing shortage of mental health providers led to a national emergency in child and adolescent mental health in the United States. The need for effective, accessible treatment is more pressing than ever. Interdisciplinary, team-based pediatric integrated mental healthcare has been shown to be efficacious, accessible, and cost-effective. METHODS: In response to the youth mental health crisis, Rady Childrens Hospital-San Diegos Transforming Mental Health Initiative aimed to increase early identification of mental illness and improve access to effective treatment for children and adolescents. A stakeholder engagement process was established with affiliated pediatric clinics, community mental health organizations, and existing pediatric integrated care programs, leading to the development of the Primary Care Mental Health Integration program and drawing from established models of integrated care: Primary Care Behavioral Health and Collaborative Care. RESULTS: As of 2023, the Primary Care Mental Health Integration program established integrated care teams in 10 primary care clinics across San Diego and Riverside counties in California. Measurement-based care has been implemented and preliminary results indicate that patient response to therapy has resulted in a 44% reduction in anxiety symptoms and a 62% decrease in depression symptoms. The program works toward fiscal sustainability via fee-for-service reimbursement and more comprehensive payor contracts. The impact on patients, primary care provider satisfaction, measurement-based care, funding strategies, as well as challenges faced and changes made will be discussed using the lens of the Reach, Effectiveness, Adoption, Implementation and Maintenance framework. DISCUSSION: Preliminary results suggest that the Primary Care Mental Health Integration is a highly collaborative integrated care model that identifies the needs of children and adolescents and delivers brief, evidence informed treatment. The successful integration of this model into 10 primary care clinics over 3 years has laid the groundwork for future program expansion. This model of care can play a role addressing youth mental health and increasing access to care. Challenges, successes, and lessons learned will be reviewed