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Abstract This case study examined how the Kingdom of Saudi Arabia (KSA) managed the 2018 Hajj season, one of the largest worldwide gatherings, to identify prominent communication strategies utilised in a large event. The two-way symmetrical communication and the renewal discourse theory served as theoretical frameworks. A thematic analysis was utilised to analyse communication content, news articles, and tweets. It is almost impossible to know whether the KSA intentionally applied Grunig’s two-way symmetrical communications theory; nevertheless, the results suggested that KSA operated in a way that followed Grunig’s theory. The findings showed how the KSA learned from past mistakes and incorporated Grunig’s two-way symmetrical communication model to implement best public relations practices for a successful 2018 Hajj season. This case study provided various perspectives on how employing communication strategies can help manage a significant event successfully.

Abstract Our research investigates the relationship between economic and social development indicators and the prevalence of impunity within a country. As countries develop, their institutions tend to function more efficiently and impartially, resulting in less impunity as crimes and violations are more efficiently investigated and prosecuted. We describe a country’s level of economic and social development along seven dimensions and use such a description in a beta regression analysis to predict the level of impunity in 119 countries. We estimate the elasticities of impunity with respect to the variables representing the different dimensions of economic and social progress. We present plots with the estimated elasticity curves for scenarios indicative of less and more socially and economically developed societies and also for the scenario indicative of societies in transition between the two groups. We also identify the countries with the best and worst performance in terms of their levels of impunity in relation to the levels of the conditioning variables. It is shown that Nordic countries exhibit lower impunity than expected based on their economic and social development factors. Conversely, the United States displays a significantly higher level of impunity than expected from its development indicators.

Abstract Researchers have an obligation to study aspects of our world that have meaning for society. This means recognising a place-based diversity of society, of potential participants, of types of participation and of knowledge production. Therefore, developing a successful community science (CS) programme that engenders a sense of ownership for a diversity of public participants requires the prioritisation of getting to know what diverse participants value and the context of that valuation. This paper describes the necessary rigour of considering the launch of the CS programme Soilsafe Aotearoa (SA) in 2021, and its subsequent implementation and evolution based on a project commitment to diversity of social values of soil in Aotearoa New Zealand (Aotearoa NZ), delivering on public demand. We discuss how SA engages with the community by scientific screening soil metal contaminants in participants’ backyards, as well as through inclusive education and knowledge co-production in schools and community spaces. The objective in this work is to generate wider participation and dialogue on a diversity of soil value(s) so that communities in Aotearoa NZ are cognisant of what soil might represent to others, and to contextualise what a lack of soil care might mean for them and society more broadly. Here we argue that a diversity of participants and participation can support a more inclusive and contextual, place-based CS approach. We illustrate how that might be achieved through bridging arts, Indigenous knowledge production, and social, as well as conventional sciences. Through an approach that recognises that values about the world are tied to participants’ geographic, demographic and cultural contexts as well as the sectors of society they work and live with, we demonstrate the importance of researchers’ attention to not just scientific enquiry, but intersections of different knowledge production and communication for better societal and science outcomes.

Abstract Researchers and policymakers hold diverse opinions about the impact of globalization on environmental degradation. Over the past three decades, increased economic, social, and political interconnections have fueled this debate. However, prior studies have largely overlooked these facets of globalization concerning environmental implications, particularly carbon emissions in developing countries. We contribute to this discourse by examining how various aspects of globalization (economic, social, and political) and two specific measures, de facto and de jure trade, influenced carbon emissions in four selected South Asian countries from 1996 to 2019. The results obtained through feasible generalized least squares (FGLS) reveal that economic globalization increases carbon emissions while social and political globalization reduces them. These results further confirm that, in South Asia, the pollution haven hypothesis is associated only with economic globalization. In contrast, social and political globalization support the world polity theory, indicating potential for positive change. The results also show that both de facto and de jure measures of disaggregated globalization equally influence carbon emissions, suggesting a significant impact from policy interventions. For future environmental sustainability, the governments of these nations should intensify their efforts to strengthen social and political globalization. Meanwhile, the adverse effects of economic globalization can be mitigated by reducing reliance on fossil fuels and providing financial assistance to businesses to encourage the use of renewable energy and modern technology in production.

Abstract This study aims to explore the perspectives of community leaders (CL) on trusted sources of health information, examine their roles, challenges, and needs in disseminating COVID-19 health information, and identify opportunities to improve public health reach and access for underserved communities. This qualitative study included seven focus groups conducted via online video conferencing from April-June 2021. The participants (n = 9) were CL recruited from the Texas Community Engagement Alliance (CEAL) for their experience working with underserved communities in Dallas, Texas. Data were coded deductively and analyzed thematically. The analysis resulted in three themes: (1) Information fatigue, mistrust, and desensitization were experienced by community members and leaders; (2) CL were expected to process, verify, and share accurate and timely COVID-19 health information; (3) CL identified potential strategies to improve COVID-19 health info access and reach. CLs were critical in addressing mis/disinformation and fostering trust in public health communication, particularly in underserved communities. They acted as vital intermediaries for health information, striving to debunk mis/disinformation and disseminate accurate health information. Public health strategies could benefit from prioritizing the integration of CL in communicating health information during crises and rebuilding trust within historically and racially marginalized and underserved communities. Supporting CLs, for example, through resources and training programs to counter misinformation and provide access to culturally and linguistically tailored health resources, may significantly enhance the access and reach of evidence-based health communication during health crises.

Abstract The current study examines how careless online behavior and personality traits are related to the detection of fake news. We tested the relationships among accurately distinguishing between fake and real news headlines, careless online behavioral tendencies, and the HEXACO and dark triad personality traits. Poorer discernment between fake and real news headlines was associated with greater careless behavior online (i.e., greater online disinhibition, greater risky online behavior, greater engagement with strangers online, and less suspicion of others’ intentions online), as well as lower Conscientiousness, Openness, and Honesty-Humility, and greater dark triad traits. Implications for the literature as well as potential interventions to reduce susceptibility to misinformation and fake news are discussed.

Abstract This study introduces StreetTalk, an original qualitative research methodology inspired by social media influencers, to investigate perceptions and experiences of energy insecurity among New York City (NYC) residents. Briefly, energy insecurity is defined as difficulty meeting household energy needs due to affordability, housing quality, outages and coping strategies. This present study employs dynamic short-form interviews with 34 participants from all five NYC boroughs of diverse economic, and racial/ethnic backgrounds. Thematic analysis of video-recorded interviews revealed six major energy insecurity-related categories: (1) conservation and trade-offs, (2) physical inefficiencies, (3) thermal agency, (4) response to the bill, (5) disappointment and distrust in energy-related authorities, and (6) desire for and barriers to clean energy adoption. These themes provide insight into NYC residents’ experiences with energy insecurity and are consistent with prior research. Beyond new scholarly insights, this study introduces StreetTalk, an innovative qualitative research methodology emphasizing rapid data collection and dissemination through social media platforms, including TikTok, Instagram, Facebook, and YouTube (@hotandcold_nyc). Taking advantage of modern technology and modes of communication, the research team was able to effectively break down barriers to academic research consumption as the videos achieved substantial engagement, with almost 200,000 views and impressions within the first year of launching this novel street-based data collection and social media dissemination campaign.

Abstract Achieving complete tumor resection is challenging and can be improved by real-time fluorescence-guided surgery with molecular-targeted probes. However, pre-clinical identification and validation of probes presents a lengthy process that is traditionally performed in animal models and further hampered by inter- and intra-tumoral heterogeneity in target expression. To screen multiple probes at patient scale, we developed a multispectral real-time 3D imaging platform that implements organoid technology to effectively model patient tumor heterogeneity and, importantly, healthy human tissue binding.

Abstract Targeted intracellular delivery of therapeutic proteins remains a significant unmet challenge in biotechnology. A promising approach is to leverage the intrinsic capabilities of bacterial toxins like diphtheria toxin (DT) to deliver a potent cytotoxic enzyme into cells with an associated membrane translocation moiety. Despite showing promising clinical efficacy, widespread deployment of DT-based therapeutics is complicated by the prevalence of pre-existing antibodies in the general population arising from childhood DT toxoid vaccinations, which impact the exposure, efficacy, and safety of these potent molecules. Here, we describe the discovery and characterization of a distant DT homolog from the ancient reptile pathogen Austwickia chelonae that we have dubbed chelona toxin (ACT). We show that ACT is comparable to DT structure and function in all respects except that it is not recognized by pre-existing anti-DT antibodies circulating in human sera. Furthermore, we demonstrate that ACT delivers heterologous therapeutic cargos into target cells more efficiently than DT. Our findings highlight ACT as a promising new chassis for building next-generation immunotoxins and targeted delivery platforms with improved pharmacokinetic and pharmacodynamic properties.

Abstract While whole genome sequencing (WGS) of cell-free DNA (cfDNA) holds enormous promise for detection of molecular residual disease (MRD), its performance is limited by WGS error rate. Here we introduce AccuScan, an efficient cfDNA WGS technology that enables genome-wide error correction at single read-level, achieving an error rate of 4.2 × 10−7, which is about two orders of magnitude lower than a read-centric de-noising method. The application of AccuScan to MRD demonstrated analytical sensitivity down to 10−6 circulating variant allele frequency at 99% sample-level specificity. AccuScan showed 90% landmark sensitivity (within 6 weeks after surgery) and 100% specificity for predicting relapse in colorectal cancer. It also showed 67% sensitivity and 100% specificity in esophageal cancer using samples collected within one week after surgery. When AccuScan was applied to monitor immunotherapy in melanoma patients, the circulating tumor DNA (ctDNA) levels and dynamic profiles were consistent with clinical outcomes. Overall, AccuScan provides a highly accurate WGS solution for MRD detection, empowering ctDNA detection at parts per million range without requiring high sample input or personalized reagents.

Abstract There is growing support and interest in postsecondary interdisciplinary environmental education, which integrates concepts and disciplines in addition to providing varied perspectives. There is a need to assess student learning in these programs as well as rigorous evaluation of educational practices, especially of complex synthesis concepts. This work tests a text classification machine learning model as a tool to assess student systems thinking capabilities using two questions anchored by the Food-Energy-Water (FEW) Nexus phenomena by answering two questions (1) Can machine learning models be used to identify instructor-determined important concepts in student responses? (2) What do college students know about the interconnections between food, energy, and water, and how have students assimilated systems thinking into their constructed responses about FEW? Reported here is a broad range of model performances across 26 text classification models associated with two different assessment items, with model accuracy ranging from 0.755 to 0.992. Expert-like responses were infrequent in our dataset compared to responses providing simpler, incomplete explanations of the systems presented in the question. For those students moving from describing individual effects to multiple effects, their reasoning about the mechanism behind the system indicates advanced systems thinking ability. Specifically, students exhibit higher expertise in explaining changing water usage than discussing trade-offs for such changing usage. This research represents one of the first attempts to assess the links between foundational, discipline-specific concepts and systems thinking ability. These text classification approaches to scoring student FEW Nexus Constructed Responses (CR) indicate how these approaches can be used, in addition to several future research priorities for interdisciplinary, practice-based education research. Development of further complex question items using machine learning would allow evaluation of the relationship between foundational concept understanding and integration of those concepts as well as a more nuanced understanding of student comprehension of complex interdisciplinary concepts.

Abstract In humans, blood Classical CD14+ monocytes contribute to host defense by secreting large amounts of pro-inflammatory cytokines. Their aberrant activity causes hyper-inflammation and life-threatening cytokine storms, while dysfunctional monocytes are associated with ‘immunoparalysis’, a state of immune hypo responsiveness and reduced pro-inflammatory gene expression, predisposing individuals to opportunistic infections. Understanding how monocyte functions are regulated is critical to prevent these harmful outcomes. We reveal platelets’ vital role in the pro-inflammatory cytokine responses of human monocytes. Naturally low platelet counts in patients with immune thrombocytopenia or removal of platelets from healthy monocytes result in monocyte immunoparalysis, marked by impaired cytokine response to immune challenge and weakened host defense transcriptional programs. Remarkably, supplementing monocytes with fresh platelets reverses these conditions. We discovered that platelets serve as reservoirs of key cytokine transcription regulators, such as NF-κB and MAPK p38, and pinpointed the enrichment of platelet NF-κB2 in human monocytes by proteomics. Platelets proportionally restore impaired cytokine production in human monocytes lacking MAPK p38α, NF-κB p65, and NF-κB2. We uncovered a vesicle-mediated platelet-monocyte-propagation of inflammatory transcription regulators, positioning platelets as central checkpoints in monocyte inflammation.

Abstract Proximity labeling (PL) via biotinylation coupled with mass spectrometry (MS) captures spatial proteomes in cells. Large-scale processing requires a workflow minimizing hands-on time and enhancing quantitative reproducibility. We introduced a scalable PL pipeline integrating automated enrichment of biotinylated proteins in a 96-well plate format. Combining this with optimized quantitative MS based on data-independent acquisition (DIA), we increased sample throughput and improved protein identification and quantification reproducibility. We applied this pipeline to delineate subcellular proteomes across various compartments. Using the 5HT2A serotonin receptor as a model, we studied temporal changes of proximal interaction networks induced by receptor activation. In addition, we modified the pipeline for reduced sample input to accommodate CRISPR-based gene knockout, assessing dynamics of the 5HT2A network in response to perturbation of selected interactors. This PL approach is universally applicable to PL proteomics using biotinylation-based PL enzymes, enhancing throughput and reproducibility of standard protocols.

Abstract Growth in the green jobs sector has increased demand for college graduates who are prepared to enter the workforce with interdisciplinary sustainability skills. Simultaneously, scholarly calls for interdisciplinary collaboration in the service of addressing the societal challenges of enhancing resilience and sustainability have also increased in recent years. However, developing, executing, and assessing interdisciplinary content and skills at the post-secondary level has been challenging. The objective of this paper is to offer the Food-Energy-Water (FEW) Nexus as a powerful way to achieve sustainability competencies and matriculate graduates who will be equipped to facilitate the transformation of the global society by meeting the targets set by the United Nations Sustainable Development Goals. The paper presents 10 curricular design examples that span multiple levels, including modules, courses, and programs. These modules enable clear evaluation and assessment of key sustainability competencies, helping to prepare graduates with well-defined skillsets who are equipped to address current and future workforce needs.

Abstract The variability of proteins at the sequence level creates an enormous potential for proteome complexity. Exploring the depths and limits of this complexity is an ongoing goal in biology. Here, we systematically survey human and plant high-throughput bottom-up native proteomics data for protein truncation variants, where substantial regions of the full-length protein are missing from an observed protein product. In humans, Arabidopsis, and the green alga Chlamydomonas, approximately one percent of observed proteins show a short form, which we can assign by comparison to RNA isoforms as either likely deriving from transcript-directed processes or limited proteolysis. While some detected protein fragments align with known splice forms and protein cleavage events, multiple examples are previously undescribed, such as our observation of fibrocystin proteolysis and nuclear translocation in a green alga. We find that truncations occur almost entirely between structured protein domains, even when short forms are derived from transcript variants. Intriguingly, multiple endogenous protein truncations of phase-separating translational proteins resemble cleaved proteoforms produced by enteroviruses during infection. Some truncated proteins are also observed in both humans and plants, suggesting that they date to the last eukaryotic common ancestor. Finally, we describe novel proteoform-specific protein complexes, where the loss of a domain may accompany complex formation.

Abstract The design of effective teamwork teaching and learning for multidisciplinary student teams is subject to debate both in research as well as in practice. As researchers and educators, we need to understand the context in which students learn by understanding their experiences and their own conceptualizations of teamwork in multidisciplinary student teams, because that is the frame of reference in which they operate. Using a concept mapping method we aggregated student concept maps of their own teamwork, to understand student conceptualizations of teamwork. The results show that students identify four distinct clusters, the ‘interaction’ cluster, the ‘trust’ cluster, the ‘conflict/divergence’ cluster and the ‘innovation’ cluster. These clusters are strongly connected within themselves, but very weakly connected between clusters. What may be gathered from this is that students see four distinct aspects of teamwork, that have their own inner dynamics, but that is less clear to them how these different clusters influence or mediate each other.

Abstract Transdisciplinary co-produced health research and co-designed interventions have the capacity to improve research quality and the relevance, acceptability, and accessibility of healthcare. This approach also helps researchers to address power imbalances to share decision-making with service-users and the public. However, this growing methodology is currently difficult to appraise and develop as detailed sharing of practice is limited. The ‘CO-production of a Nature-based Intervention For children with ADHD study’ (CONIFAS) aimed to create a novel intervention with and for children with attention deficit hyperactivity disorder (ADHD) using co-production and co-design methodologies. This knowledge exchange paper will be of benefit to researchers with aspirations to undertake co-production, especially in the context of working with under-represented groups. Critical reflection on the use of co-production identified that every attempt was made to adequately resource the co-production, share power, value diversity, and develop trust. The team reflected that the re-conceptualisation of the role of the researcher in co-production can be challenging. Whilst the use of models of co-production provides a framework for study development, designing and running the specifics of the workshops, as well as how to effectively engage co-researchers in an equitable way, came from utilising clinical skills, networking, and creativity. These methods are particularly pertinent to involving neurodiverse children and their families who are under-represented in participatory research and in need of bespoke health interventions.

Abstract Necroptosis is a lytic form of regulated cell death reported to contribute to inflammatory diseases of the gut, skin and lung, as well as ischemic-reperfusion injuries of the kidney, heart and brain. However, precise identification of the cells and tissues that undergo necroptotic cell death in vivo has proven challenging in the absence of robust protocols for immunohistochemical detection. Here, we provide automated immunohistochemistry protocols to detect core necroptosis regulators – Caspase-8, RIPK1, RIPK3 and MLKL – in formalin-fixed mouse and human tissues. We observed surprising heterogeneity in protein expression within tissues, whereby short-lived immune barrier cells were replete with necroptotic effectors, whereas long-lived cells lacked RIPK3 or MLKL expression. Local changes in the expression of necroptotic effectors occurred in response to insults such as inflammation, dysbiosis or immune challenge, consistent with necroptosis being dysregulated in disease contexts. These methods will facilitate the precise localisation and evaluation of necroptotic signaling in vivo.

Abstract The road from transcription to protein synthesis is paved with many obstacles, allowing for several modes of post-transcriptional regulation of gene expression. A fundamental player in mRNA biology is DDX3X, an RNA binding protein that canonically regulates mRNA translation. By monitoring dynamics of mRNA abundance and translation following DDX3X depletion, we observe stabilization of translationally suppressed mRNAs. We use interpretable statistical learning models to uncover GC content in the coding sequence as the major feature underlying RNA stabilization. This result corroborates GC content-related mRNA regulation detectable in other studies, including hundreds of ENCODE datasets and recent work focusing on mRNA dynamics in the cell cycle. We provide further evidence for mRNA stabilization by detailed analysis of RNA-seq profiles in hundreds of samples, including a Ddx3x conditional knockout mouse model exhibiting cell cycle and neurogenesis defects. Our study identifies a ubiquitous feature underlying mRNA regulation and highlights the importance of quantifying multiple steps of the gene expression cascade, where RNA abundance and protein production are often uncoupled.

Abstract Vaccination has successfully controlled several infectious diseases although better vaccines remain desirable. Host response to vaccination studies have identified correlates of vaccine immunogenicity that could be useful to guide development and selection of future vaccines. However, it remains unclear whether these findings represent mere statistical correlations or reflect functional associations with vaccine immunogenicity. Functional associations, rather than statistical correlates, would offer mechanistic insights into vaccine-induced adaptive immunity. Through a human experimental study to test the immunomodulatory properties of metformin, an anti-diabetic drug, we chanced upon a functional determinant of neutralizing antibodies. Although vaccine viremia is a known correlate of antibody response, we found that in healthy volunteers with no detectable or low yellow fever 17D viremia, metformin-treated volunteers elicited higher neutralizing antibody titers than placebo-treated volunteers. Transcriptional and metabolomic analyses collectively showed that a brief course of metformin, started 3 days prior to YF17D vaccination and stopped at 3 days after vaccination, expanded oxidative phosphorylation and protein translation capacities. These increased capacities directly correlated with YF17D neutralizing antibody titers, with reduced reactive oxygen species response compared to placebo-treated volunteers. Our findings thus demonstrate a functional association between cellular respiration and vaccine-induced humoral immunity and suggest potential approaches to enhancing vaccine immunogenicity.

The escalating challenge of antimicrobial resistance (AMR) has led to a surge of global research and policy discourse on refilling an empty antibiotic pipeline. The empty pipeline metaphor is, however, wrought with paradoxes. Drawing on critical social sciences and humanities research on pharmaceutical innovation, this comment article presents five of the key paradoxes that structure contemporary innovation discourse: Was the so-called “Golden Age” of antibiotics really golden? Was rational drug design truly rational in terms of antibiotic development? Was the antibiotic pipeline really built on a foundation of scientific breakthroughs by an elite group of (male) inventors? How can antibiotics, powerful symbols of industrial power, be considered as market failures? How could the crisis of antibiotics become the golden hour of their policing? Rather than dissect each paradox, the article aims to complicate standard problem diagnoses and encourage creative new conceptualizations of inclusive antimicrobial innovation.

Abstract System avoidance is a concept that individual contact with the criminal legal system causes avoidance of other social institutions. Negative attitudes about the criminal legal system and subsequent mistrust in healthcare systems or providers have only been studied in adults. Therefore, the aim of this study is to explore the association between healthcare utilization and youth-reported negative criminal legal attitudes stratified by gender and race in adolescents. Adolescents from the Future of Families and Child Wellbeing Study self-reported attitudes involving legal cynicism, police legitimacy, and healthcare utilization. Logistic regressions were estimated to examine the associations between youth-reported criminal legal attitudes involving legal cynicism and police legitimacy, healthcare utilization, and sociodemographics. Only among non-white girls were negative criminal legal attitudes significantly associated with reduced likelihood of healthcare utilization during the previous 12 months (aOR = 0.55, p ≤ 0.01). Negative criminal legal attitudes in non-white girls reduced the odds of healthcare utilization, which supports the concept of system avoidance of institutions. This has implications for policymakers as they enact laws on crime and surveillance, especially in minority communities, as views on the criminal legal institution can impact other facets of life. More research is needed to directly explore this relationship beyond cross-sectional studies.

Abstract Vaccination with infectious Plasmodium falciparum (Pf) sporozoites (SPZ) administered with antimalarial drugs (PfSPZ-CVac), confers superior sterilizing protection against infection when compared to vaccination with replication-deficient, radiation-attenuated PfSPZ. However, the requirement for drug administration constitutes a major limitation for PfSPZ-CVac. To obviate this limitation, we generated late liver stage-arresting replication competent (LARC) parasites by deletion of the Mei2 and LINUP genes (mei2 – /linup – or LARC2). We show that Plasmodium yoelii (Py) LARC2 sporozoites did not cause breakthrough blood stage infections and engendered durable sterilizing immunity against various infectious sporozoite challenges in diverse strains of mice. We next genetically engineered a PfLARC2 parasite strain that was devoid of extraneous DNA and produced cryopreserved PfSPZ-LARC2. PfSPZ-LARC2 liver stages replicated robustly in liver-humanized mice but displayed severe defects in late liver stage differentiation and did not form liver stage merozoites. This resulted in complete abrogation of parasite transition to viable blood stage infection. Therefore, PfSPZ-LARC2 is the next-generation vaccine strain expected to unite the safety profile of radiation-attenuated PfSPZ with the superior protective efficacy of PfSPZ-CVac.

Abstract Complex disease phenotypes often span multiple molecular processes. Functional characterization of these processes can shed light on disease mechanisms and drug effects. Thermal Proteome Profiling (TPP) is a mass-spectrometry (MS) based technique assessing changes in thermal protein stability that can serve as proxies of functional protein changes. These unique insights of TPP can complement those obtained by other omics technologies. Here, we show how TPP can be integrated with phosphoproteomics and transcriptomics in a network-based approach using COSMOS, a multi-omics integration framework, to provide an integrated view of transcription factors, kinases and proteins with altered thermal stability. This allowed us to recover consequences of Poly (ADP-ribose) polymerase (PARP) inhibition in ovarian cancer cells on cell cycle and DNA damage response as well as interferon and hippo signaling. We found that TPP offers a complementary perspective to other omics data modalities, and that its integration allowed us to obtain a more complete molecular overview of PARP inhibition. We anticipate that this strategy can be used to integrate functional proteomics with other omics to study molecular processes.

Abstract The MECHANISMS study investigates how social norms for adolescent smoking and vaping are transmitted through school friendship networks, and is the first study to use behavioral economics methodology to assess smoking-related social norms. Here, we investigate the effects of selection homophily (the tendency to form friendships with similar peers) and peer influence (a social process whereby an individual’s behavior or attitudes are affected by peers acting as reference points for the individual) on experimentally measured smoking and vaping norms, and other smoking outcomes, in adolescents from high and middle-income settings. Full school year groups in six secondary schools in Northern Ireland (United Kingdom) and six secondary schools in Bogotá (Colombia) participated (n = 1344/1444, participation = 93.1%, target age 12–13 years). Over one semester, pupils received one previously tested school-based smoking prevention program (ASSIST or Dead Cool). Outcomes included experimentally measured smoking/vaping norms, self-report and objectively measured smoking behavior, and self-report smoking norms, intentions, susceptibility, attitudes, and psycho-social antecedents. We investigated selection homophily and peer influence using regressions and SIENA modeling. Regression results demonstrate lagged and contemporaneous selection homophily (odds ratios [ORs] = 0.87–1.26, p ≤ 0.01), and peer influence effects for various outcomes from average responses of friends, school classes, or school year groups (standardized coefficients [βs] = 0.07–0.55, ORs = 1.14–1.31, p ≤ 0.01). SIENA models showed that comparable proportions of smoking/vaping-based similarity between friends were due to selection homophily (32.8%) and peer influence (39.2%). A higher percentage of similarity between friends was due to selection homophily and/or peer influence for ASSIST schools compared to Dead Cool. Selection homophily was also more important in Bogotá, whilst peer influence was stronger in Northern Ireland. These findings support using social norms strategies in adolescent smoking prevention interventions. Future research should consider selection homophily and social influence jointly, and examine whether these findings translate to other high and low-middle-income settings with varying cultures and norms.

Abstract Communications between immune cells are essential to ensure appropriate coordination of their activities. Here, we observed the infiltration of activated macrophages into the joint-footpads of chikungunya virus (CHIKV)-infected animals. Large numbers of CD64+MHCII+ and CD64+MHCII- macrophages were present in the joint-footpad, preceded by the recruitment of their CD11b+Ly6C+ inflammatory monocyte precursors. Recruitment and differentiation of these myeloid subsets were dependent on CD4+ T cells and GM-CSF. Transcriptomic and gene ontology analyses of CD64+MHCII+ and CD64+MHCII- macrophages revealed 89 differentially expressed genes, including genes involved in T cell proliferation and differentiation pathways. Depletion of phagocytes, including CD64+MHCII+ macrophages, from CHIKV-infected mice reduced disease pathology, demonstrating that these cells play a pro-inflammatory role in CHIKV infection. Together, these results highlight the synergistic dynamics of immune cell crosstalk in driving CHIKV immunopathogenesis. This study provides new insights in the disease mechanism and offers opportunities for development of novel anti-CHIKV therapeutics.

Abstract TP53-mutant acute myeloid leukemia (AML) and myelodysplastic neoplasms (MDS) are characterized by chemotherapy resistance and represent an unmet clinical need. Chimeric antigen receptor (CAR) T-cells might be a promising therapeutic option for TP53-mutant AML/MDS. However, the impact of TP53 deficiency in AML cells on the efficacy of CAR T-cells is unknown. We here show that CAR T-cells engaging TP53-deficient leukemia cells exhibit a prolonged interaction time, upregulate exhaustion markers, and are inefficient to control AML cell outgrowth in vitro and in vivo compared to TP53 wild-type cells. Transcriptional profiling revealed that the mevalonate pathway is upregulated in TP53-deficient AML cells under CAR T-cell attack, while CAR T-cells engaging TP53-deficient AML cells downregulate the Wnt pathway. In vitro rational targeting of either of these pathways rescues AML cell sensitivity to CAR T-cell-mediated killing. We thus demonstrate that TP53 deficiency confers resistance to CAR T-cell therapy and identify the mevalonate pathway as a therapeutic vulnerability of TP53-deficient AML cells engaged by CAR T-cells, and the Wnt pathway as a promising CAR T-cell therapy-enhancing approach for TP53-deficient AML/MDS.

Abstract The academic literature on personal experiences of climate-induced wellbeing erosion (often conceptualised as ‘non-economic losses and damages’) is still limited. This represents a serious climate policy gap that hinders support for marginalised people across the world including Indigenous People. Lately, we have seen a rapid growth in empirical studies exploring linkages between climate change and mental health among Indigenous Inuit in Canada. However, its association with human (im)mobility remains unexplored. This review article brings together the empirical evidence of Inuit experiences and perceptions of climate-related wellbeing loss and (im)mobility while providing climate policy with guidance for appropriate action. The systematic review investigates how Inuit in Arctic Canada felt that climatic changes impacted their (im)mobility and mental health while putting these feelings into a wider context of colonial violence, forced child removal, the residential schools, and other systematic human rights abuses. Twelve electronic databases (four specific to Arctic research) were searched for English and French, peer reviewed, qualitative studies published between 2000 and 2021. Fifteen selected articles were analysed using NVivo and thematic narrative analysis from a climate-violence-health nexus systems approach. Three overarching climate-related wellbeing loss themes, all strongly intertwined with feelings of immobility, emerged from the literature namely ‘identity and cultural loss’, ‘land connection as a source of healing’, and ‘changing environment triggering emotional distress’. The narratives circled around Inuit land connection and how climate-induced temporary (im)mobility interrupted this relationship. Climatic changes isolated Inuit away from the land and cut off their ability to partake in land activities. This strongly eroded Inuit wellbeing, expressed through distress, anxiety, depression, social tension, suicide ideation and deep feelings of cultural loss. The findings showed how Inuit mental health strongly depend on a sustained connection to the land. Further empirical research among other Indigenous People or nomadic groups on wellbeing loss and climate-induced involuntary immobility is urgently needed. Future research should particularly explore how such mental health impacts tie into past and present (post)colonial traumas and current suicide occurrences. This will help climate policy, research, and adaptation planning better prepare and propose more contextually and culturally appropriate health actions in the future.

Abstract Our knowledge of the geography of medieval religious dissent and its repression in the Latin West is limited by a lack of systematic study of locational information in inquisition trial records. Spatial analysis of these rich details has the potential to help build a bottom-up picture of interaction between dissidents and inquisitors that moves beyond institutional perspectives. This task is rendered challenging due to the inconsistencies and uncertainties of what inquisitors and their notaries typically recorded about the spatial associations of suspects. Probably the most common indicator of such associations found in inquisition records are toponymic surnames. They present challenges of coverage (not everybody had a toponymic surname) and interpretation (multiple possible meanings). This study attempts to tackle the challenge of interpreting such surnames within the context of the nine sentencing events held by the inquisitor Peter Seila in 1241 and 1242 in the Quercy region of Languedoc: covering 650 sentenced individuals, the register documenting these events is the earliest extant record of an inquisition of such scale. Rather than taking the interpretative challenges of toponymic surnames as reasons to limit ourselves to qualitative analysis, our approach shows the value of rendering and analysing them as structured data. Firstly, we quantify the context of toponymic surnames, placing them against the background of broader name construction practices and other social factors. Secondly, we plot and analyse the geocoded data derived from toponymic surnames with the benefit of this contextualisation, looking especially at the distance of toponyms from their associated sentencing centres, in order to derive narratives that best explain the generality of their meaning. The results allow us to appraise the actual spatial coverage of the nine sentencing events. The first two, centred on the important towns of Montauban and Moissac, seem most likely to have been primarily urban affairs, with little evidence of rural coverage. The remainder, which took place in castra (fortified villages), appear to have covered more of the surrounding countryside. These results geographically contextualise the reports of dissidence conveyed within Peter’s register, and suggest narratives for how Peter optimised his strategy for impact in the face of constraints.

Abstract The affective well-being of employees is significant in today’s fast-paced lifestyle in the post-pandemic era, as it results in many benefits, including work-related and health-related benefits. It is known that the positive reflection of work predicts the affective well-being of employees. However, the optimal ways of strengthening the relationship between these variables in contemporary working conditions are yet to be explored. Drawing on border theory and implicit theories, this research analyzes the role of work contact and growth mindset in the relationship between positive work reflection and affective well-being. In addition, this study proposes a three-way interaction among positive work reflection, work contact, and growth mindset in predicting the affective well-being of employees. Responses were collected from employees working in IT firms. After screening, 309 valid samples were obtained. From the analysis, it was found that a higher level of work contact moderates the relationship between positive work reflection and the affective well-being of employees with a growth mindset. Alternatively, a medium level of work contact moderates the above relationship for both types of mindset (growth and fixed mindset) among employees.

Abstract Structural resolution of protein interactions enables mechanistic and functional studies as well as interpretation of disease variants. However, structural data is still missing for most protein interactions because we lack computational and experimental tools at scale. This is particularly true for interactions mediated by short linear motifs occurring in disordered regions of proteins. We find that AlphaFold-Multimer predicts with high sensitivity but limited specificity structures of domain-motif interactions when using small protein fragments as input. Sensitivity decreased substantially when using long protein fragments or full length proteins. We delineated a protein fragmentation strategy particularly suited for the prediction of domain-motif interfaces and applied it to interactions between human proteins associated with neurodevelopmental disorders. This enabled the prediction of highly confident and likely disease-related novel interfaces, which we further experimentally corroborated for FBXO23-STX1B, STX1B-VAMP2, ESRRG-PSMC5, PEX3-PEX19, PEX3-PEX16, and SNRPB-GIGYF1 providing novel molecular insights for diverse biological processes. Our work highlights exciting perspectives, but also reveals clear limitations and the need for future developments to maximize the power of Alphafold-Multimer for interface predictions.

Abstract College student voter turnout reflects the degree to which students are being taught to support and protect democracy, long a core mission of the U.S. higher education system. Yet, college student voter turnout is generally very low. In 2020–2021, campuses around the country participated in a coordinated program to increase college student voter registration during the COVID-19 pandemic. Using survey and focus group data collected in spring 2021, we find evidence of understudied barriers to student registration that continue to restrict the effectiveness of those efforts. Specifically, we find that students need help determining whether or how to choose a political party affiliation and whether to register with their campus address. Efforts to help students surmount these understudied challenges are a potentially powerful means of increasing youth registration and turnout. We also find that students operated as knowledge brokers, sharing with family members the information they were receiving on campus about how to register and vote using new virtual options offered due to the pandemic.

Abstract Although clinical applications represent the next challenge in single-cell genomics and digital pathology, we still lack computational methods to analyze single-cell or pathomics data to find sample-level trajectories or clusters associated with diseases. This remains challenging as single-cell/pathomics data are multi-scale, i.e., a sample is represented by clusters of cells/structures, and samples cannot be easily compared with each other. Here we propose PatIent Level analysis with Optimal Transport (PILOT). PILOT uses optimal transport to compute the Wasserstein distance between two individual single-cell samples. This allows us to perform unsupervised analysis at the sample level and uncover trajectories or cellular clusters associated with disease progression. We evaluate PILOT and competing approaches in single-cell genomics or pathomics studies involving various human diseases with up to 600 samples/patients and millions of cells or tissue structures. Our results demonstrate that PILOT detects disease-associated samples from large and complex single-cell or pathomics data. Moreover, PILOT provides a statistical approach to find changes in cell populations, gene expression, and tissue structures related to the trajectories or clusters supporting interpretation of predictions.

Abstract Adaptation studies in media have been carried out for decades since the 1950s. When media is adapted between different forms, the narrative inherently changes; even more so when they cross a cultural divide between Japan and the United States. That is precisely the topic of discussion between the anime Ghost in the Shell (1995) and its live action film adaptation Ghost in the Shell (2017). With narrative being a key focus for comparison in this article, Joseph Campbell’s Hero’s Journey is applied. Taken from his seminal work Hero with a Thousand Faces, the theory of the Hero’s Journey has been the go-to reference for monomyth studies for decades which identifies the parallelism and common themes in diverse stories, from classic myths embedded in ancient cultures to film and other contemporary media based on popular culture. Yet, most studies stop there, and do not consider bringing in Campbell’s other works—namely his follow-up collection of books The Masks of God which delves deeper into the mythologies of various regions. His books, Oriental Mythology and Occidental Mythology, zeroes in on the myths in the East and West, which would aid in conducting comparisons between materials originating from the two opposite regions, further supplementing its usefulness in adaptation studies concerning Japanese anime and their corresponding Hollywood adaptations. This article covers the changes in narrative themes corresponding to Campbell’s Oriental and Occidental mythology between the anime Ghost in the Shell (1995) and its live action film adaptation Ghost in the Shell (2017).

Abstract Effective integration and implementation of knowledge in research are dependent on team science expertise grounded in collaboration principles and techniques that advance individual and group scientific agendas. The Science of Team Science (SciTS) provides evidence-based research and best practices that strive to develop scientists’ collaborative skills so that they can work across disciplinary boundaries while developing strong and diverse teaming relationships. Identifying the motivations of those involved in collaborative teaming can contribute to maximizing team effectiveness and applying the knowledge emerging from understanding these to shape teams’ adaptation of a shared mutual learning mindset as a core tenet of scientific teamwork. In addition, surfacing motivations has the potential of helping team members examine their own needs in relation to their scientific and career goals. In this paper we draw from the domains of the Motivation Assessment for Team, Readiness, Integration, and Collaboration (MATRICx) framework, Maslow’s Hierarchy of Needs motivational theory, and The Team Effectiveness Model for Science (TEMS) to develop a Reflective-Reflexive Design Method (R2DM) that focuses on the development of intra-personal attributes within the context of a team. Approaching expertise development from this design method invites individual reflection in the context of group reflexivity to serve as the cornerstone of deep team science expertise. We used a design thinking approach to identify a framework that merges individual reflection with group reflexivity. The core questions we asked are: (i) What constitutes expertise to succeed in science teams? and (ii) How might we approach the design of learning engagements that enable the development of the needed expertise?

Abstract Cell‐free DNA (cfDNA) can be isolated and sequenced from blood and/or urine of cancer patients. Conventional short‐read sequencing lacks deployability and speed and can be biased for short cfDNA fragments. Here, we demonstrate that with Oxford Nanopore Technologies (ONT) sequencing we can achieve delivery of genomic and fragmentomic data from liquid biopsies. Copy number aberrations and cfDNA fragmentation patterns can be determined in less than 24 h from sample collection. The tumor‐derived cfDNA fraction calculated from plasma of lung cancer patients and urine of bladder cancer patients was highly correlated (R = 0.98) with the tumor fraction calculated from short‐read sequencing of the same samples. cfDNA size profile, fragmentation patterns, fragment‐end composition, and nucleosome profiling near transcription start sites in plasma and urine exhibited the typical cfDNA features. Additionally, a high proportion of long tumor‐derived cfDNA fragments (> 300 bp) are recovered in plasma and urine using ONT sequencing. ONT sequencing is a cost‐effective, fast, and deployable approach for obtaining genomic and fragmentomic results from liquid biopsies, allowing the analysis of previously understudied cfDNA populations.

Abstract Brain tumors are the leading cause of cancer‐related death in children. Experimental in vitro models that faithfully capture the hallmarks and tumor heterogeneity of pediatric brain cancers are limited and hard to establish. We present a protocol that enables efficient generation, expansion, and biobanking of pediatric brain cancer organoids. Utilizing our protocol, we have established patient‐derived organoids (PDOs) from ependymomas, medulloblastomas, low‐grade glial tumors, and patient‐derived xenograft organoids (PDXOs) from medulloblastoma xenografts. PDOs and PDXOs recapitulate histological features, DNA methylation profiles, and intratumor heterogeneity of the tumors from which they were derived. We also showed that PDOs can be xenografted. Most interestingly, when subjected to the same routinely applied therapeutic regimens, PDOs respond similarly to the patients. Taken together, our study highlights the potential of PDOs and PDXOs for research and translational applications for personalized medicine.

Abstract Following peripheral nerve injury, successful axonal growth and functional recovery require Schwann cell (SC) reprogramming into a reparative phenotype, a process dependent upon c‐Jun transcription factor activation. Unfortunately, axonal regeneration is greatly impaired in aged organisms and following chronic denervation, which can lead to poor clinical outcomes. While diminished c‐Jun expression in SCs has been associated with regenerative failure, it is unclear whether the inability to maintain a repair state is associated with the transition into an axonal growth inhibition phenotype. We here find that reparative SCs transition into a senescent phenotype, characterized by diminished c‐Jun expression and secretion of inhibitory factors for axonal regeneration in aging and chronic denervation. In both conditions, the elimination of senescent SCs by systemic senolytic drug treatment or genetic targeting improved nerve regeneration and functional recovery, increased c‐Jun expression and decreased nerve inflammation. This work provides the first characterization of senescent SCs and their influence on axonal regeneration in aging and chronic denervation, opening new avenues for enhancing regeneration and functional recovery after peripheral nerve injuries.

Abstract Glioblastoma (GBM) remains the most malignant primary brain tumor, with a median survival rarely exceeding 2 years. Tumor heterogeneity and an immunosuppressive microenvironment are key factors contributing to the poor response rates of current therapeutic approaches. GBM‐associated macrophages (GAMs) often exhibit immunosuppressive features that promote tumor progression. However, their dynamic interactions with GBM tumor cells remain poorly understood. Here, we used patient‐derived GBM stem cell cultures and combined single‐cell RNA sequencing of GAM‐GBM co‐cultures and real‐time in vivo monitoring of GAM‐GBM interactions in orthotopic zebrafish xenograft models to provide insight into the cellular, molecular, and spatial heterogeneity. Our analyses revealed substantial heterogeneity across GBM patients in GBM‐induced GAM polarization and the ability to attract and activate GAMs—features that correlated with patient survival. Differential gene expression analysis, immunohistochemistry on original tumor samples, and knock‐out experiments in zebrafish subsequently identified LGALS1 as a primary regulator of immunosuppression. Overall, our work highlights that GAM‐GBM interactions can be studied in a clinically relevant way using co‐cultures and avatar models, while offering new opportunities to identify promising immune‐modulating targets.

Abstract This study investigates the association between CEOs’ overconfidence and future earnings management. This research is designed to explain CEOs’ overconfidence with the serial logic of self-confidence and self-identity in constructing their overconfidence. The authors demonstrate the CEOs’ overconfidence using multiple measures exploratorily that criticise their behaviour to manage their firms’ earnings aggressively. The authors collected data from the Bureau Van Dijk and Refinitiv Thomson Reuters databases. They identified manufacturing firms listed on the stock exchanges of Singapore (SSE), Malaysia (KLSE), Thailand (SET), the Philippines (PSE), Indonesia (IDX), Vietnam (HOSE), Pakistan (PSE); Taiwan (TSEC); India (NSE) and China (SSE). They categorised developing countries as lower-middle and upper-middle-income. This study used Generalised Least-Square (GLS) regression to test all the hypotheses. This study finds this association robust in an international setting for developing countries. In other words, it shows some extant research that most CEOs in developing countries would intentionally like to manage future earnings. Furthermore, it identifies developing countries with lower-middle incomes and less competition due to emerging capital markets. Then, it highlights that CEOs in developing countries tend to be overconfident because of cognitive behaviour. Moreover, these CEOs assemble an organisational culture that can easily improve prospective performance. Therefore, this study infers that economic uncertainty causes CEOs to be overconfident, enhancing their boldness when managing earnings excessively. This study presents a novelty supported by three critical reasoning arguments. First, it explains the phenomenon of CEOs’ overconfidence through self-confidence (self-control). Second, the authors develop multiple measurements used in the study to mark the CEOs’ overconfidence as a combined product of self-confidence and self-identity. It uses capital expenditures to measure the CEOs’ overconfidence and firm overinvestment, the incremental debt-to-equity ratio, historical earnings persistence, historical stock price persistence, the magnitude of the related party’s transactions and political connections. Third, this study investigates CEOs’ overconfidence in an international setting.

Abstract Recent advances in multiplexed single‐cell transcriptomics experiments facilitate the high‐throughput study of drug and genetic perturbations. However, an exhaustive exploration of the combinatorial perturbation space is experimentally unfeasible. Therefore, computational methods are needed to predict, interpret, and prioritize perturbations. Here, we present the compositional perturbation autoencoder (CPA), which combines the interpretability of linear models with the flexibility of deep‐learning approaches for single‐cell response modeling. CPA learns to in silico predict transcriptional perturbation response at the single‐cell level for unseen dosages, cell types, time points, and species. Using newly generated single‐cell drug combination data, we validate that CPA can predict unseen drug combinations while outperforming baseline models. Additionally, the architecture's modularity enables incorporating the chemical representation of the drugs, allowing the prediction of cellular response to completely unseen drugs. Furthermore, CPA is also applicable to genetic combinatorial screens. We demonstrate this by imputing in silico 5,329 missing combinations (97.6% of all possibilities) in a single‐cell Perturb‐seq experiment with diverse genetic interactions. We envision CPA will facilitate efficient experimental design and hypothesis generation by enabling in silico response prediction at the single‐cell level and thus accelerate therapeutic applications using single‐cell technologies.

Abstract Prostate cancer is the most commonly diagnosed malignancy and the third leading cause of cancer deaths. GWAS have identified variants associated with prostate cancer susceptibility; however, mechanistic and functional validation of these mutations is lacking. We used CRISPR‐Cas9 genome editing to introduce a missense variant identified in the ELAC2 gene, which encodes a dually localised nuclear and mitochondrial RNA processing enzyme, into the mouse Elac2 gene as well as to generate a prostate‐specific knockout of Elac2. These mutations caused enlargement and inflammation of the prostate and nodule formation. The Elac2 variant or knockout mice on the background of the transgenic adenocarcinoma of the mouse prostate (TRAMP) model show that Elac2 mutation with a secondary genetic insult exacerbated the onset and progression of prostate cancer. Multiomic profiling revealed defects in energy metabolism that activated proinflammatory and tumorigenic pathways as a consequence of impaired noncoding RNA processing and reduced protein synthesis. Our physiologically relevant models show that the ELAC2 variant is a predisposing factor for prostate cancer and identify changes that underlie the pathogenesis of this cancer.

Abstract Metabolism is controlled to ensure organismal development and homeostasis. Several mechanisms regulate metabolism, including allosteric control and transcriptional regulation of metabolic enzymes and transporters. So far, metabolism regulation has mostly been described for individual genes and pathways, and the extent of transcriptional regulation of the entire metabolic network remains largely unknown. Here, we find that three‐quarters of all metabolic genes are transcriptionally regulated in the nematode Caenorhabditis elegans. We find that many annotated metabolic pathways are coexpressed, and we use gene expression data and the iCEL1314 metabolic network model to define coregulated subpathways in an unbiased manner. Using a large gene expression compendium, we determine the conditions where subpathways exhibit strong coexpression. Finally, we develop “WormClust,” a web application that enables a gene‐by‐gene query of genes to view their association with metabolic (sub)‐pathways. Overall, this study sheds light on the ubiquity of transcriptional regulation of metabolism and provides a blueprint for similar studies in other organisms, including humans.

Abstract Infections with rabies virus (RABV) and related lyssaviruses are uniformly fatal once virus accesses the central nervous system (CNS) and causes disease signs. Current immunotherapies are thus focused on the early, pre‐symptomatic stage of disease, with the goal of peripheral neutralization of virus to prevent CNS infection. Here, we evaluated the therapeutic efficacy of F11, an anti‐lyssavirus human monoclonal antibody (mAb), on established lyssavirus infections. We show that a single dose of F11 limits viral load in the brain and reverses disease signs following infection with a lethal dose of lyssavirus, even when administered after initiation of robust virus replication in the CNS. Importantly, we found that F11‐dependent neutralization is not sufficient to protect animals from mortality, and a CD4 T cell‐dependent adaptive immune response is required for successful control of infection. F11 significantly changes the spectrum of leukocyte populations in the brain, and the FcRγ‐binding function of F11 contributes to therapeutic efficacy. Thus, mAb therapy can drive potent neutralization‐independent T cell‐mediated effects, even against an established CNS infection by a lethal neurotropic virus.

Abstract Hematopoietic cell transplantation (HCT) treats many blood conditions but remains underused due to complications such as graft‐versus‐host disease (GvHD). In GvHD, donor immune cells attack the patient, requiring powerful immunosuppressive drugs like glucocorticoids (GCs) to prevent death. In this study, we tested the hypothesis that donor cell conditioning with the glucocorticoid fluticasone propionate (FLU) prior to transplantation could increase hematopoietic stem cell (HSC) engraftment and reduce GvHD. Murine HSCs treated with FLU had increased HSC engraftment and reduced severity and incidence of GvHD after transplantation into allogeneic hosts. While most T cells died upon FLU treatment, donor T cells repopulated in the hosts and appeared less inflammatory and alloreactive. Regulatory T cells (Tregs) are immunomodulatory and survived FLU treatment, resulting in an increased ratio of Tregs to conventional T cells. Our results implicate an important role for Tregs in maintaining allogeneic tolerance in FLU‐treated grafts and suggest a therapeutic strategy of pre‐treating donor cells (and not the patients directly) with GCs to simultaneously enhance engraftment and reduce GvHD upon allogeneic HCT.

Abstract SARS‐CoV‐2 acute respiratory distress syndrome (ARDS) induces uncontrolled lung inflammation and coagulopathy with high mortality. Anti‐viral drugs and monoclonal antibodies reduce early COVID‐19 severity, but treatments for late‐stage immuno‐thrombotic syndromes and long COVID are limited. Serine protease inhibitors (SERPINS) regulate activated proteases. The myxoma virus‐derived Serp‐1 protein is a secreted immunomodulatory serpin that targets activated thrombotic, thrombolytic, and complement proteases as a self‐defense strategy to combat clearance. Serp‐1 is effective in multiple animal models of inflammatory lung disease and vasculitis. Here, we describe systemic treatment with purified PEGylated Serp‐1 as a therapy for immuno‐coagulopathic complications during ARDS. Treatment with PEGSerp‐1 in two mouse‐adapted SARS‐CoV‐2 models in C57Bl/6 and BALB/c mice reduced lung and heart inflammation, with improved outcomes. PEGSerp‐1 significantly reduced M1 macrophages in the lung and heart by modifying urokinase‐type plasminogen activator receptor (uPAR), thrombotic proteases, and complement membrane attack complex (MAC). Sequential changes in gene expression for uPAR and serpins (complement and plasminogen inhibitors) were observed. PEGSerp‐1 is a highly effective immune‐modulator with therapeutic potential for severe viral ARDS, immuno‐coagulopathic responses, and Long COVID.

Abstract The ongoing degradation of natural systems and other environmental changes has put our society at a crossroad with respect to our future relationship with our planet. While the concept of One Health describes how human health is inextricably linked with environmental health, many of these complex interdependencies are still not well‐understood. Here, we describe how the advent of real‐time genomic analyses can benefit One Health and how it can enable timely, in‐depth ecosystem health assessments. We introduce nanopore sequencing as the only disruptive technology that currently allows for real‐time genomic analyses and that is already being used worldwide to improve the accessibility and versatility of genomic sequencing. We showcase real‐time genomic studies on zoonotic disease, food security, environmental microbiome, emerging pathogens, and their antimicrobial resistances, and on environmental health itself – from genomic resource creation for wildlife conservation to the monitoring of biodiversity, invasive species, and wildlife trafficking. We stress why equitable access to real‐time genomics in the context of One Health will be paramount and discuss related practical, legal, and ethical limitations.

Graphical Abstract Osteogenesis imperfecta (OI) is a hereditary skeletal disorder primarily affecting collagen type I structure and function, causing bone fragility and occasionally versatile extraskeletal symptoms. This study expands the spectrum of OI‐causing TAPT1 mutations and links extracellular matrix changes to signaling regulation.

Abstract This study aimed to identify microbial signatures that contribute to the shared etiologies between chronic heart failure (CHF), type 2 diabetes, and chronic kidney disease. The serum levels of 151 microbial metabolites were measured in 260 individuals from the Risk Evaluation and Management of heart failure cohort, and it was found that those metabolites varied by an order of 105 fold. Out of 96 metabolites associated with the three cardiometabolic diseases, most were validated in two geographically independent cohorts. In all three cohorts, 16 metabolites including imidazole propionate (ImP) consistently showed significant differences. Notably, baseline ImP levels were three times higher in the Chinese compared with the Swedish cohorts and increased by 1.1–1.6 fold with each additional CHF comorbidity in the Chinese population. Cellular experiments further supported a causal link between ImP and distinct CHF relevant phenotypes. Additionally, key microbial metabolite‐based risk scores were superior in CHF prognosis than the traditional Framingham or Get with the Guidelines‐Heart Failure risk scores. Interactive visualization of these specific metabolite‐disease links is available on our omics data server ( https://omicsdata.org/Apps/REM‐HF/ ).