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The present study examined how the expression of enhanced green fluorescent protein (eGFP) and human cardiac actin (ACTC) in zebrafish Danio rerio influences embryonic heart rate ( RH) and the swim performance and metabolic rate of adult fish. Experiments with the adults involved determining the critical swimming speed ( Ucrit, the highest speed sustainable and measure of aerobic capacity) while measuring oxygen consumption. Two different transgenic D. rerio lines were examined: one expressed eGFP in the heart ( tg(cmlc:egfp)), while the second expressed ACTC in the heart and eGFP throughout the body ( tg(cmlc:actc,ba:egfp)). It was found that RH was significantly lower in the tg(cmlc:actc,ba:egfp) embryos 4 days post-fertilization compared to wild-type (WT) and tg(cmlc:egfp). The swim experiments demonstrated that there was no significant difference in Ucrit between the transgenic lines and the wild-type fish, but metabolic rate and cost of transport (oxygen used to travel a set distance) was nearly two-fold higher in the tg(cmlc:actc,ba:egfp) fish compared to WT at their respective Ucrit. These results suggest that the expression of ACTC in the D. rerio heart and the expression of eGFP throughout the animal, alters cardiac function in the embryo and reduces the aerobic efficiency of the animal at high levels of activity. [ABSTRACT FROM AUTHOR]

The role of long noncoding RNAs (lncRNAs) in disease is incompletely understood, but their regulation of inflammation is increasingly appreciated. We addressed the extent of lncRNA involvement in inflammatory bowel disease (IBD) using biopsy-derived RNA-sequencing data from a large cohort of deeply phenotyped patients with IBD. Weighted gene correlation network analysis revealed gene modules of lncRNAs coexpressed with protein-coding genes enriched for biological pathways, correlated with epithelial and immune cell signatures, or correlated with distal colon expression. Correlation of modules with clinical features uncovered a module correlated with disease severity, with an enriched interferon response signature containing the hub lncRNA IRF1-AS1. Connecting genes to IBD-associated single nucleotide polymorphisms (SNPs) revealed an enrichment of SNP-adjacent lncRNAs in biologically relevant modules. Ulcerative colitis-specific SNPs were enriched in distal colon-related modules, suggesting that disease-specific mechanisms may result from altered lncRNA expression. The function of the IBD-associated SNP-adjacent lncRNA IRF1-AS1 was explored in human myeloid cells, and our results suggested IRF1-AS1 promoted optimal production of TNF-α, IL-6, and IL-23. A CRISPR/Cas9-mediated activation screen in THP-1 cells revealed several lncRNAs that modulated LPS-induced TNF-α responses. Overall, this study uncovered the expression patterns of lncRNAs in IBD that identify functional, disease-relevant lncRNAs.

Remote inflammation monitoring with digital health technologies (DHTs) would provide valuable information for both clinical research and care. Controlled perturbations of the immune system may reveal physiological signatures which could be used to develop a digital biomarker of inflammatory state. In this study, molecular and physiological profiling was performed following an in vivo lipopolysaccharide (LPS) challenge to develop a digital biomarker of inflammation. Ten healthy volunteers received an intravenous LPS challenge and were monitored for 24 h using the VitalConnect VitalPatch (VitalPatch). VitalPatch measurements included heart rate (HR), heart rate variability (HRV), respiratory rate (RR), and skin temperature (TEMP). Conventional episodic inpatient vital signs and serum proteins were measured pre- and post-LPS challenge. The VitalPatch provided vital signs that were comparable to conventional methods for assessing HR, RR, and TEMP. A pronounced increase was observed in HR, RR, and TEMP as well as a decrease in HRV 1-4 h post-LPS challenge. The ordering of participants by magnitude of inflammatory cytokine response 2 h post-LPS challenge was consistent with ordering of participants by change from baseline in vital signs when measured by VitalPatch (r = 0.73) but not when measured by conventional methods (r = -0.04). A machine learning model trained on VitalPatch data predicted change from baseline in inflammatory protein response (R 2  = 0.67). DHTs, such as VitalPatch, can improve upon existing episodic measurements of vital signs by enabling continuous sensing and have the potential for future use as tools to remotely monitor inflammation., (© 2024 Janssen Pharmaceutical Research and Development (Johnson & Johnson). Clinical and Translational Science published by Wiley Periodicals LLC on behalf of American Society for Clinical Pharmacology and Therapeutics.)

Background: Early and accurate identification of acute exacerbations of COPD may lead to earlier treatment and prevent hospital admission. Electronic diaries have been developed for symptom monitoring and accelerometers to monitor activity. However, it is unclear whether this technology is usable in the COPD population. This study aimed to assess the feasibility of an electronic diary (eDiary) for symptom reporting using the MoreCare app and activity monitoring with the Garmin Vivofit 2 in COPD., Methods: Participants were recruited from the London COPD Cohort. Participants were provided a Garmin Vivofit 2 activity monitor and an android tablet with the MoreCare app for a period of 3 months., Results: 25 COPD patients were recruited (mean±sd age 70.8±7.1 years, forced expiratory volume in 1 s (FEV 1 ) 49.8±14.8% predicted). Age, gender, disease severity and exacerbation frequency had no impact on eDiary compliance. There was a moderate positive correlation between median daily very active minutes and FEV 1 % pred (ρ=0.62, p=0.005). Daily step counts decreased during the initial 7 days of exacerbation and recovery compared to a pre-exacerbation baseline. A decision-tree model identified change in sputum colour, change in step count, severity of cold, exacerbation history and use of rescue medication as the most important predictors of acute exacerbations of COPD in this cohort., Conclusions: Symptom and activity monitoring using digital technology is feasible in COPD. Further large-scale digital health studies are needed to assess whether eDiaries can be used to identify patients at risk of exacerbation and guide early intervention., Competing Interests: Conflict of interest: L.J. Finney reports support for the present manuscript from Janssen R&D; grants or contracts from an NHLI Foundation Clinical Lectureship, outside the submitted work; and unpaid society board membership as a British Thoracic Society COPD Specialist Advisory Group Member, outside the submitted work. Conflict of interest: S. Avey reports support for the present manuscript from Janssen R&D and was employed by Janssen R&D during this study. Conflict of interest: A. Rowe reports support for the present manuscript from Janssen R&D and was employed by Janssen R&D during this study. Conflict of interest: M.J. Loza reports support for the present manuscript from Janssen R&D and was employed by Janssen R&D during this study. Conflict of interest: C.S. Stevenson reports support for the present manuscript from Janssen R&D and was employed by Janssen R&D during this study. Conflict of interest: F. Baribaud reports support for the present manuscript from Janssen R&D and was employed by Janssen R&D during this study. Conflict of interest: J.A. Wedzicha reports support for the present manuscript from Janssen R&D, and grants or contracts from Boehringer, AstraZeneca and GSK, outside the submitted work. Conflict of interest: I. Pandis reports support for the present manuscript from Janssen R&D and was employed by Janssen R&D during this study. Conflict of interest: The remaining authors have nothing to disclose., (Copyright ©The authors 2023.)

Background: Innovative Medicines Initiative (IMI) consortium IDEA-FAST is developing novel digital measures of fatigue, sleep quality, and impact of sleep disturbances for neurodegenerative diseases and immune-mediated inflammatory diseases. In 2022, the consortium met with the European Medicines Agency (EMA) to receive advice on its plans for regulatory qualification of the measures. This viewpoint reviews the IDEA-FAST perspective on developing digital measures for multiple diseases and the advice provided by the EMA., Summary: The EMA considered a cross-disease measure an interesting and arguably feasible concept. Developers should account for the need for a strong rationale that the clinical features to be measured are similar across diseases. In addition, they may expect increased complexity of study design, challenges when managing differences within and between disease populations, and the need for validation in both heterogeneous and homogeneous populations., Key Messages: EMA highlighted the challenges teams may encounter when developing a cross-disease measure, though benefits potentially include reduced resources for the technology developer and health authority, faster access to innovation across different therapeutic fields, and feasibility of cross-disease comparisons. The insights included here can be used by project teams to guide them in the development of cross-disease digital measures intended for regulatory qualification., Competing Interests: David Nobbs and Sebastian C. Holst are full-time employees and shareholders of F. Hoffmann-La Roche. Wojciech Piwko is a full-time employee and shareholder of Takeda Pharmaceutical Co. Ltd. Christopher Bull is a full-time employee of the University of Newcastle upon Tyne. Francesca Cormack is a full-time employee and shareholder of Cambridge Cognition Ltd. Teemu Ahmaniemi is a full-time employee of VTT Technical Research Center of Finland Ltd. Meenakshi Chatterjee and Stefan Avey are full-time employees and shareholders of Johnson & Johnson. Wan Fai Ng has provided consultation services for the following companies in the area of Sjogren’s syndrome and/or fatigue: Novartis, GlaxoSmithKline, AbbVie, BMS, Sanofi, MedImmune, argenx, Janssen, Resolve Therapeutics, Bain Capitals, and UCB., (© 2023 The Author(s). Published by S. Karger AG, Basel.)

Background: Emerging digital measures and clinical outcome assessments (COAs) leveraging digital health technologies (DHTs) could address the need for objective, quantitative measures of symptoms of atopic dermatitis (AD), such as nocturnal scratching. Development of such measures needs to be supported by evidence reflecting meaningfulness to patients., Objectives: To assess nocturnal scratching as a concept of interest associated with meaningful aspects of health of patients with AD (adults and children); and to explore patient-centred considerations for novel COAs measuring nocturnal scratch using DHTs., Methods: Phase 1 evaluated disease impacts on everyday life and the lived experience with nocturnal scratching through qualitative interviews of AD patients and caregivers. Phase 2 deployed a quantitative survey to a sample of AD patients as well as caregivers., Results: Four cohorts with various AD severity levels participated in Phase 1: (1) adults with AD ( n  = 15), (2) their caregivers/spouses/partners ( n  = 6), (3) children with AD ( n  = 14), and (4) their adult caregivers ( n  = 14). Findings were used to develop a conceptual model for nocturnal scratching as a potential concept of interest. The Phase 2 survey was completed by 1349 of 27640 invited adults with AD and caregivers of children with AD. The most burdensome aspects of AD reported were itchy skin and scratching. Overall, ∼65% of participants reported nocturnal scratching ≥1 day/week, resulting in ∼1-1.4 h of sleep lost per night. In all, 85%-91% of respondents considered it at least somewhat valuable that a treatment reduces night-time scratching. About 50% reported willingness to use technology to this end and ∼25% were unsure., Conclusion: Our results represented by the conceptual model confirm that nocturnal scratch is a concept of interest related to meaningful aspects of health for patients with AD and therefore is worth being captured as a distinct outcome for clinical and research purposes. DHTs are suitable tools presenting an important measurement opportunity to assess and evaluate occurrence, frequency, and other parameters of nocturnal scratching as a disease biomarker or COA of treatment efficacy., Competing Interests: Lucia Cesnakova and Jennifer C. Goldsack are employees of the Digital Medicine Society, the sponsor of this study. The other authors are employees of their respective organizations. Carrie A. Northcott, Doina Sirbu and Jérémy Lambert are shareholders of their respective organizations., (© 2023 Digital Medicine Society (DiME). Skin Health and Disease published by John Wiley & Sons Ltd on behalf of British Association of Dermatologists.)

The seasonal influenza vaccine is an important public health tool but is only effective in a subset of individuals. The identification of molecular signatures provides a mechanism to understand the drivers of vaccine-induced immunity. Most previously reported molecular signatures of human influenza vaccination were derived from a single age group or season, ignoring the effects of immunosenescence or vaccine composition. Thus, it remains unclear how immune signatures of vaccine response change with age across multiple seasons. In this study we profile the transcriptional landscape of young and older adults over five consecutive vaccination seasons to identify shared signatures of vaccine response as well as marked seasonal differences. Along with substantial variability in vaccine-induced signatures across seasons, we uncovered a common transcriptional signature 28 days postvaccination in both young and older adults. However, gene expression patterns associated with vaccine-induced Ab responses were distinct in young and older adults; for example, increased expression of killer cell lectin-like receptor B1 ( KLRB1 ; CD161 ) 28 days postvaccination positively and negatively predicted vaccine-induced Ab responses in young and older adults, respectively. These findings contribute new insights for developing more effective influenza vaccines, particularly in older adults., (Copyright © 2020 by The American Association of Immunologists, Inc.)

Both aging and HIV infection are associated with an enhanced pro-inflammatory environment that contributes to impaired immune responses and is mediated in part by innate immune pattern-recognition receptors. MINCLE is a C-type lectin receptor that recognizes trehalose-6,6'-dimycolate or "cord factor," the most abundant glycolipid in Mycobacterium tuberculosis. Here, we evaluated MINCLE function in monocytes in a cohort of HIV-infected and uninfected young (21-35 years) and older adults (≥60 years) via stimulation of peripheral blood mononuclear cells with trehalose-6,6-dibehenate, a synthetic analog of trehalose-6,6'-dimycolate and measurement of cytokine production (interleukin [IL]-10, IL-12, IL-6, tumor necrosis factor-α) by multicolor flow cytometry. Our studies show an age- and HIV-associated increase in cytokine multifunctionality of monocytes both at the population and single cell level that was dominated by IL-12, IL-10, and IL-6. These findings provide insight into the host response to M. tuberculosis and possible sources for the pro-inflammatory environment seen in aging and HIV infection., (© The Author(s) 2018. Published by Oxford University Press on behalf of The Gerontological Society of America. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Small sample sizes combined with high person-to-person variability can make it difficult to detect significant gene expression changes from transcriptional profiling studies. Subtle, but coordinated, gene expression changes may be detected using gene set analysis approaches. Meta-analysis is another approach to increase the power to detect biologically relevant changes by integrating information from multiple studies. Here, we present a framework that combines both approaches and allows for meta-analysis of gene sets. QuSAGE meta-analysis extends our previously published QuSAGE framework, which offers several advantages for gene set analysis, including fully accounting for gene-gene correlations and quantifying gene set activity as a full probability density function. Application of QuSAGE meta-analysis to influenza vaccination response shows it can detect significant activity that is not apparent in individual studies., Competing Interests: I have read the journal’s policy and the authors of this manuscript have the following competing interests: S.A. received personal fees from Janssen R&D while writing this manuscript. C.R.B. reports employment and equity ownership for Genentech.

Motivation: Systems immunology leverages recent technological advancements that enable broad profiling of the immune system to better understand the response to infection and vaccination, as well as the dysregulation that occurs in disease. An increasingly common approach to gain insights from these large-scale profiling experiments involves the application of statistical learning methods to predict disease states or the immune response to perturbations. However, the goal of many systems studies is not to maximize accuracy, but rather to gain biological insights. The predictors identified using current approaches can be biologically uninterpretable or present only one of many equally predictive models, leading to a narrow understanding of the underlying biology., Results: Here we show that incorporating prior biological knowledge within a logistic modeling framework by using network-level constraints on transcriptional profiling data significantly improves interpretability. Moreover, incorporating different types of biological knowledge produces models that highlight distinct aspects of the underlying biology, while maintaining predictive accuracy. We propose a new framework, Logistic Multiple Network-constrained Regression (LogMiNeR), and apply it to understand the mechanisms underlying differential responses to influenza vaccination. Although standard logistic regression approaches were predictive, they were minimally interpretable. Incorporating prior knowledge using LogMiNeR led to models that were equally predictive yet highly interpretable. In this context, B cell-specific genes and mTOR signaling were associated with an effective vaccination response in young adults. Overall, our results demonstrate a new paradigm for analyzing high-dimensional immune profiling data in which multiple networks encoding prior knowledge are incorporated to improve model interpretability., Availability and Implementation: The R source code described in this article is publicly available at https://bitbucket.org/kleinstein/logminer ., Contact: steven.kleinstein@yale.edu or stefan.avey@yale.edu., Supplementary Information: Supplementary data are available at Bioinformatics online., (© The Author 2017. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com)

Unlabelled: Influenza viruses continue to present global threats to human health. Antigenic drift and shift, genetic reassortment, and cross-species transmission generate new strains with differences in epidemiology and clinical severity. We compared the temporal transcriptional responses of human dendritic cells (DC) to infection with two pandemic (A/Brevig Mission/1/1918, A/California/4/2009) and two seasonal (A/New Caledonia/20/1999, A/Texas/36/1991) H1N1 influenza viruses. Strain-specific response differences included stronger activation of NF-κB following infection with A/New Caledonia/20/1999 and a unique cluster of genes expressed following infection with A/Brevig Mission/1/1918. A common antiviral program showing strain-specific timing was identified in the early DC response and found to correspond with reported transcript changes in blood during symptomatic human influenza virus infection. Comparison of the global responses to the seasonal and pandemic strains showed that a dramatic divergence occurred after 4 h, with only the seasonal strains inducing widespread mRNA loss., Importance: Continuously evolving influenza viruses present a global threat to human health; however, these host responses display strain-dependent differences that are incompletely understood. Thus, we conducted a detailed comparative study assessing the immune responses of human DC to infection with two pandemic and two seasonal H1N1 influenza strains. We identified in the immune response to viral infection both common and strain-specific features. Among the stain-specific elements were a time shift of the interferon-stimulated gene response, selective induction of NF-κB signaling by one of the seasonal strains, and massive RNA degradation as early as 4 h postinfection by the seasonal, but not the pandemic, viruses. These findings illuminate new aspects of the distinct differences in the immune responses to pandemic and seasonal influenza viruses., (Copyright © 2015, American Society for Microbiology. All Rights Reserved.)

Current approaches to predicting adverse effects in humans from acute toxic exposure to cosmetic ingredients still heavily necessitate the use of animals under EU legislation, particularly in the context of the REACH system, when cosmetic ingredients are also destined for use in other industries. These include the LD50 test, the Up-and-Down Procedure and the Fixed Dose Procedure, which are regarded as having notable scientific deficiencies and low transferability to humans. By expanding on previous in vitro tests, such as the animal cell-based 3T3 Neutral Red Uptake (NRU) assay, this project aims to develop a truly animal-free predictive test for the acute toxicity of cosmetic ingredients in humans, by using human-derived cells and a prediction model that does not rely on animal data. The project, funded by Innovate UK, will incorporate the NRU assay with human dermal fibroblasts in animal product-free culture, to generate an in vitro protocol that can be validated as an accepted replacement for the currently available in vivo tests. To date, the project has successfully completed an assessment of the robustness and reproducibility of the method, by using sodium lauryl sulphate (SLS) as a positive control, and displaying analogous results to those of the original studies with mouse 3T3 cells. Currently, the testing of five known ingredients from key groups (a surfactant, a preservative, a fragrance, a colour and an emulsifier) is under way. The testing consists of initial range-finding runs followed by three valid runs of a main experiment with the appropriate concentration ranges, to generate IC50 values. Expanded blind trials of 20 ingredients will follow. Early results indicate that this human cell-based test holds the potential to replace aspects of in vivo animal acute toxicity testing, particularly with reference to cosmetic ingredients., (2015 FRAME.)

A common goal of tumor sequencing projects is finding genes whose mutations are selected for during tumor development. This is accomplished by choosing genes that have more non-synonymous mutations than expected from an estimated background mutation frequency. While this background frequency is unknown, it can be estimated using both the observed synonymous mutation frequency and the non-synonymous to synonymous mutation ratio. The synonymous mutation frequency can be determined across all genes or in a gene-specific manner. This choice introduces an interesting trade-off. A gene-specific frequency adjusts for an underlying mutation bias, but is difficult to estimate given missing synonymous mutation counts. Using a genome-wide synonymous frequency is more robust, but is less suited for adjusting biases. Studying four evaluation criteria for identifying genes with high non-synonymous mutation burden (reflecting preferential selection of expressed genes, genes with mutations in conserved bases, genes with many protein interactions, and genes that show loss of heterozygosity), we find that the gene-specific synonymous frequency is superior in the gene expression and protein interaction tests. In conclusion, the use of the gene-specific synonymous mutation frequency is well suited for assessing a gene's non-synonymous mutation burden.