MARS an improved de novo peptide candidate selection method for non-canonical antigen target discovery in cancer.

Understanding the nature and extent of non-canonical human leukocyte antigen (HLA) presentation in tumour cells is a priority for target antigen discovery for the development of next generation immunotherapies in cancer. We here employ a de novo mass spectrometric sequencing approach with a refined, MHC-centric analysis strategy to detect non-canonical MHC-associated peptides specific to cancer without any prior knowledge of the target sequence from genomic or RNA sequencing data. Our strategy integrates MHC binding rank, Average local confidence scores, and peptide Retention time prediction for improved de novo candidate Selection; culminating in the machine learning model MARS. We benchmark our model on a large synthetic peptide library dataset and reanalysis of a published dataset of high-quality non-canonical MHC-associated peptide identifications in human cancer. We achieve almost 2-fold improvement for high quality spectral assignments in comparison to de novo sequencing alone with an estimated accuracy of above 85.7% when integrated with a stepwise peptide sequence mapping strategy. Finally, we utilize MARS to detect and validate lncRNA-derived peptides in human cervical tumour resections, demonstrating its suitability to discover novel, immunogenic, non-canonical peptide sequences in primary tumour tissue.

Using collective intelligence methods to improve government data infrastructures and promote the use of complex data: The example of the Northern Ireland Longitudinal Study.

BACKGROUND: This paper discusses how collective intelligence (CI) methods can be implemented to improve government data infrastructures, not only to support understanding and primary use of complex national data but also to increase the dissemination and secondary impact of research based on these data. The case study uses the Northern Ireland Longitudinal Study (NILS), a member of the UK family of census/administrative data longitudinal studies (UKLS). METHODS: A stakeholder-engaged CI approach was applied to inform the transformation of the NILS Research Support Unit (RSU) infrastructure to support researchers in their use of government data, including collaborative decision-making and better dissemination of research outputs. RESULTS: We provide an overview of NILS RSU infrastructure design changes that have been implemented to date, focusing on a website redesign to meet user information requirements and the formation of better working partnerships between data users and providers within the Northern Ireland data landscape. We also discuss the key challenges faced by the design team during this project of transformation. CONCLUSION: Our primary objective to improve government data infrastructure and to increase dissemination and the impact of research based on data was a complex and multifaceted challenge due to the number of stakeholders involved and their often conflicting perspectives. Results from this CI approach have been pivotal in highlighting how NILS RSU can work collaboratively with users to maximize the potential of this data, in terms of forming multidisciplinary networks to ensure the research is utilized in policy and in the literature and providing academic support and resources to attract new researchers.

Cryptic MHC-E epitope from influenza elicits a potent cytolytic T cell response.

The extent to which unconventional forms of antigen presentation drive T cell immunity is unknown. By convention, CD8 T cells recognize viral peptides, or epitopes, in association with classical major histocompatibility complex (MHC) class I, or MHC-Ia, but immune surveillance can, in some cases, be directed against peptides presented by nonclassical MHC-Ib, in particular the MHC-E proteins (Qa-1 in mice and HLA-E in humans); however, the overall importance of nonclassical responses in antiviral immunity remains unclear. Similarly uncertain is the importance of 'cryptic' viral epitopes, defined as those undetectable by conventional mapping techniques. Here we used an immunopeptidomic approach to search for unconventional epitopes that drive T cell responses in mice infected with influenza virus A/Puerto Rico/8/1934. We identified a nine amino acid epitope, termed M-SL9, that drives a co-immunodominant, cytolytic CD8 T cell response that is unconventional in two major ways: first, it is presented by Qa-1, and second, it has a cryptic origin, mapping to an unannotated alternative reading frame product of the influenza matrix gene segment. Presentation and immunogenicity of M-SL9 are dependent on the second AUG codon of the positive sense matrix RNA segment, suggesting translation initiation by leaky ribosomal scanning. During influenza virus A/Puerto Rico/8/1934 infection, M-SL9-specific T cells exhibit a low level of egress from the lungs and strong differentiation into tissue-resident memory cells. Importantly, we show that M-SL9/Qa-1-specific T cells can be strongly induced by messenger RNA vaccination and that they can mediate antigen-specific cytolysis in vivo. Our results demonstrate that noncanonical translation products can account for an important fraction of the T cell repertoire and add to a growing body of evidence that MHC-E-restricted T cells could have substantial therapeutic value.

Innate immune mechanisms of mRNA vaccines.

The lipid nanoparticle (LNP)-encapsulated, nucleoside-modified mRNA platform has been used to generate safe and effective vaccines in record time against COVID-19. Here, we review the current understanding of the manner whereby mRNA vaccines induce innate immune activation and how this contributes to protective immunity. We discuss innate immune sensing of mRNA vaccines at the cellular and intracellular levels and consider the contribution of both the mRNA and the LNP components to their immunogenicity. A key message that is emerging from recent observations is that the LNP carrier acts as a powerful adjuvant for this novel vaccine platform. In this context, we highlight important gaps in understanding and discuss how new insight into the mechanisms underlying the effectiveness of mRNA-LNP vaccines may enable tailoring mRNA and carrier molecules to develop vaccines with greater effectiveness and milder adverse events in the future.

Chronic pain self-management in middle-aged and older adults: A collective intelligence approach to identifying barriers and user needs in eHealth interventions.

Objectives: eHealth refers to health services and health information delivered or enhanced through the internet and related technologies. The number of eHealth interventions for chronic pain self-management is increasing. However, little evidence has been found for the overall efficacy of these interventions for older adults. The aim of the current study was to use a Collective Intelligence approach to identify the barriers and specific user needs of middle-aged and older adults using eHealth for chronic pain self-management. Methods: A Collective Intelligence workshop was conducted with middle-aged and older adults to generate, clarify, select, and structure ideas in relation to barriers to eHealth use and specific design requirements for the purposes of chronic pain self-management. Prior to attending the workshop, participants received a trigger question requesting the identification of five barriers to eHealth use for chronic pain self-management. These barriers were categorised and presented to the group along with barrier-related scenarios and user need prompts, resulting in the generation of a set of ranked barriers and a set of user needs. Results: A total of 78 barriers were identified, from which six categories emerged: Content, Support, Technological, Personal, Computer Literacy and Accessibility. Additional idea-writing and group reflection in response to these barriers revealed 97 user needs. Conclusion: This is the first study to use Collective Intelligence methods to investigate barriers to eHealth technology use and the specific user needs of middle-aged and older adults in the context of chronic pain self-management. The results of the current study provide a platform for the design and development of enhanced eHealth interventions for this population.

mRNA Vaccines in the COVID-19 Pandemic and Beyond.

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the cause of coronavirus disease 2019 (COVID-19), emerged in China in December 2019 and quickly spread around the globe, killing more than 4 million people and causing a severe economic crisis. This extraordinary situation prompted entities in government, industry, and academia to work together at unprecedented speed to develop safe and effective vaccines. Indeed, vaccines of multiple types have been generated in record time, and many have been evaluated in clinical trials. Of these, messenger RNA (mRNA) vaccines have emerged as lead candidates due to their speed of development and high degree of safety and efficacy. To date, two mRNA vaccines have received approval for human use, providing proof of the feasibility of this next-generation vaccine modality. This review gives a detailed overview about the types of mRNA vaccines developed for SARS-CoV-2, discusses and compares preclinical and clinical data, gives a mechanistic overview about immune responses generated by mRNA vaccination, and speculates on the challenges and promising future of this emergent vaccine platform.

Enhancing the implementation and sustainability of fundamental movement skill interventions in the UK and Ireland: lessons from collective intelligence engagement with stakeholders.

BACKGROUND: To have population-level impact, physical activity (PA) interventions must be effectively implemented and sustained under real-world conditions. Adequate Fundamental Movement Skills (FMS) is integral to children being able to actively participate in play, games, and sports. Yet, few FMS interventions have been implemented at scale, nor sustained in routine practice, and thus it is important to understand the influences on sustained implementation. The study's aim was to use Collective Intelligence (CI)-an applied systems science approach-with stakeholder groups to understand barriers to the implementation of FMS interventions, interdependencies between these barriers, and options to overcome the system of barriers identified. METHODS: Three CI sessions were conducted with three separate groups of experienced FMS intervention researchers/practitioners (N = 22) in the United Kingdom and Ireland. Participants generated and ranked barriers they perceive most critical in implementing FMS interventions. Each group developed a structural model describing how highly ranked barriers are interrelated in a system. Participants then conducted action mapping to solve the problem based on the logical relations between barriers reflected in the model. RESULTS: The top ranked barriers (of 76) are those related to policy, physical education curriculum, and stakeholders' knowledge and appreciation. As reflected in the structural model, these barriers have influences over stakeholders' efficacy in delivering and evaluating interventions. According to this logical structure, 38 solutions were created as a roadmap to inform policy, practice, and research. Collectively, solutions suggest that efforts in implementation and sustainability need to be coordinated (i.e., building interrelationship with multiple stakeholders), and a policy or local infrastructure that supports these efforts is needed. CONCLUSIONS: The current study is the first to describe the complexity of barriers to implementing and sustaining FMS interventions and provide a roadmap of actions that help navigate through the complexity. By directing attention to the ecological context of FMS intervention research and participation, the study provides researchers, policy makers, and practitioners with a framework of critical components and players that need to be considered when designing and operationalising future projects in more systemic and relational terms.

Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.

The development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we show that mRNA-LNP immunization compared to protein immunization elicits either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope or HIV-1 Env gp160 induces durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 µg are immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

Using Collective Intelligence to identify barriers to implementing and sustaining effective Fundamental Movement Skill interventions: A rationale and application example.

To have population-level impact, interventions must be effectively implemented and sustained under real-world conditions. Few Fundamental Movement Skill (FMS) interventions are implemented at scale, and even fewer are sustained in a way that allows for ongoing evaluation. There has been increasing recognition of applying systems thinking to investigate the multitude of influences on interventions. To improve research-practice translations, investigations need to incorporate synthesised perspective and collective input from intervention stakeholders. This study trials Collective Intelligence (CI) - an applied systems science approach - to understand barriers to the adoption, implementation and institutionalisation of effective FMS interventions for children and adolescents. A total of 58 barriers were generated and organised into 13 barrier categories. Participants voted to select 10 critical barriers and generated a structural map among the barriers to guide future action mapping. Barriers related to Government and Institutional factors and Curricular Conflicts were structured as fundamental drivers of the system of barriers. By presenting this application example, we aim to underline the considerations and alleviate barriers to conducting much needed implementation and sustainability studies in FMS interventions. CI also adds to the "tool box" to understand the complexity and functioning of public health interventions, such as those targeting physical activity behaviours.

SARS-CoV-2 mRNA Vaccines Foster Potent Antigen-Specific Germinal Center Responses Associated with Neutralizing Antibody Generation.

The deployment of effective vaccines against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) is critical to eradicate the coronavirus disease 2019 (COVID-19) pandemic. Many licensed vaccines confer protection by inducing long-lived plasma cells (LLPCs) and memory B cells (MBCs), cell types canonically generated during germinal center (GC) reactions. Here, we directly compared two vaccine platforms-mRNA vaccines and a recombinant protein formulated with an MF59-like adjuvant-looking for their abilities to quantitatively and qualitatively shape SARS-CoV-2-specific primary GC responses over time. We demonstrated that a single immunization with SARS-CoV-2 mRNA, but not with the recombinant protein vaccine, elicited potent SARS-CoV-2-specific GC B and T follicular helper (Tfh) cell responses as well as LLPCs and MBCs. Importantly, GC responses strongly correlated with neutralizing antibody production. mRNA vaccines more efficiently induced key regulators of the Tfh cell program and influenced the functional properties of Tfh cells. Overall, this study identifies SARS-CoV-2 mRNA vaccines as strong candidates for promoting robust GC-derived immune responses.

The Eudaimonic Functions of Music Listening Scale: An Instrument to Measure Transcendence, Flow and Peak Experience in Music.

There are many adaptive functions of music listening (AFML) that are relevant for understanding wellbeing. Functions relating to mood and emotion regulation dominate general measures of music listening functions. Eudaimonic functions of music listening (FML) have been identified, but no scale has been developed to measure these functions. The current study reports on the development of a new measure to assess eudaimonic music listening functions. Items were developed based on a prior qualitative study and a literature review focused on music listening and wellbeing. The factor structure was investigated by EFA and CFA in a large sample of participants (N = 637, 17-66 years, M = 22.04, SD = 6.23, 326 males). Tests of dimensionality revealed a three factor scale with seven items. The scale and its subscales possess good internal consistency. The Eudaimonic FML scale measures Transcendence, Flow, and Peak Experience. Contrary to expectations eudaimonic FML did not relate to higher wellbeing (higher positive affect, lower negative affect, higher life satisfaction), rather results suggest that these FML are associated with greater emotional experience more generally. This brief scale will have applications in research focused on music listening benefits, music selection preferences, and experimental and developmental effects of music listening on psychological outcomes.

Understanding the Nature of Oneness Experience in Meditators Using Collective Intelligence Methods.

Research on meditation and mindfulness practice has flourished in recent years. While much of this research has focused on well-being outcomes associated with mindfulness practice, less research has focused on how perception of self may change as a result of mindfulness practice, or whether these changes in self-perception may be mechanisms of mindfulness in action. This is somewhat surprising given that mindfulness derives from traditions often described as guiding people to realize and experience the non-separation of self from the world or its "oneness" with the whole of reality. The current study used a collective intelligence methodology, Interactive Management (IM), to explore the nature of oneness experiences. Five IM sessions were conducted with five separate groups of experienced meditators. Participants generated, clarified, and selected oneness self-perceptions they believed most characterized their experience both during meditation and in their everyday experience in the world. Each group also developed structural models describing how highly ranked aspects of oneness self-perceptions are interrelated in a system. Consistent themes and categories of oneness experience appeared across the five IM sessions, with changes in the sense of space (unboundedness), time, identity, wholeness, and flow highlighted as most influential. Results are discussed in light of emerging theory and research on oneness self-perception and non-dual awareness.

A Single Immunization with Nucleoside-Modified mRNA Vaccines Elicits Strong Cellular and Humoral Immune Responses against SARS-CoV-2 in Mice.

SARS-CoV-2 infection has emerged as a serious global pandemic. Because of the high transmissibility of the virus and the high rate of morbidity and mortality associated with COVID-19, developing effective and safe vaccines is a top research priority. Here, we provide a detailed evaluation of the immunogenicity of lipid nanoparticle-encapsulated, nucleoside-modified mRNA (mRNA-LNP) vaccines encoding the full-length SARS-CoV-2 spike protein or the spike receptor binding domain in mice. We demonstrate that a single dose of these vaccines induces strong type 1 CD4+ and CD8+ T cell responses, as well as long-lived plasma and memory B cell responses. Additionally, we detect robust and sustained neutralizing antibody responses and the antibodies elicited by nucleoside-modified mRNA vaccines do not show antibody-dependent enhancement of infection in vitro. Our findings suggest that the nucleoside-modified mRNA-LNP vaccine platform can induce robust immune responses and is a promising candidate to combat COVID-19.

Recent advances in mRNA vaccine technology.

Messenger RNA (mRNA) vaccines represent a relatively new vaccine class showing great promise for the future. This optimism is built on recently published studies demonstrating the efficacy of mRNA vaccines in combatting several types of cancer and infectious pathogens where conventional vaccine platforms may fail to induce protective immune responses. These results would not have been possible without critical recent innovations in the field, such as the development of safe and efficient materials for in vivo mRNA delivery and advanced protocols for the production of high quality mRNA. This review summarizes the most important developments in mRNA vaccines from the past few years and discusses the challenges and future directions for the field.

Collaborative positive psychology: solidarity, meaning, resilience, wellbeing, and virtue in a time of crisis.

This paper introduces readers to collaborative positive psychology, a natural complement to transdisciplinary systems science. Consistent with second wave positive psychology models (PP2.0), collaborative positive psychology highlights how negative emotions (e.g. sadness, guilt, shame, anger, anxiety) can act as key drivers of positive transformation in collaborative groups, providing a catalyst for critical systems thinking and collective responses to shared problems. Collaborative positive psychology emphasises pathways from the recognition of collective problems to problem-focused and method-driven responding supporting sustainable wellbeing. Key principles of collaborative PP include solidarity, empowerment, and teamwork, with a specific focus on the application of collective intelligence (CI) methods to address shared complex problems. An overview of the work of the Collective Intelligence Network Support Unit (CINSU) is used to highlight the power and potential of collaborative groups. Collaborative positive psychology highlights the need for the development of collaborative infrastructures that reinforce solidarity, collective empowerment, and collective intelligence.

Lipid nanoparticle encapsulated nucleoside-modified mRNA vaccines elicit polyfunctional HIV-1 antibodies comparable to proteins in nonhuman primates.

Development of an effective AIDS vaccine remains a challenge. Nucleoside-modified mRNAs formulated in lipid nanoparticles (mRNA-LNP) have proved to be a potent mode of immunization against infectious diseases in preclinical studies, and are being tested for SARS-CoV-2 in humans. A critical question is how mRNA-LNP vaccine immunogenicity compares to that of traditional adjuvanted protein vaccines in primates. Here, we found that mRNA-LNP immunization compared to protein immunization elicited either the same or superior magnitude and breadth of HIV-1 Env-specific polyfunctional antibodies. Immunization with mRNA-LNP encoding Zika premembrane and envelope (prM-E) or HIV-1 Env gp160 induced durable neutralizing antibodies for at least 41 weeks. Doses of mRNA-LNP as low as 5 µg were immunogenic in macaques. Thus, mRNA-LNP can be used to rapidly generate single or multi-component vaccines, such as sequential vaccines needed to protect against HIV-1 infection. Such vaccines would be as or more immunogenic than adjuvanted recombinant protein vaccines in primates.

Does Listening to Music Regulate Negative Affect in a Stressful Situation? Examining the Effects of Self-Selected and Researcher-Selected Music Using Both Silent and Active Controls.

BACKGROUND: Stress and anxiety are increasingly common among young people. The current research describes two studies comparing the effects of self-selected and researcher-selected music on induced negative affect (state anxiety and physiological arousal), and state mindfulness. METHOD: In Study 1, 70 undergraduates were randomly assigned to one of three conditions: researcher-selected music, self-selected music, or a silent control condition. In Study 2, with 75 undergraduates, effects of music were compared to an active control (listening to a radio show). Negative affect was induced using a speech preparation and arithmetic task, followed by music listening or control. Self-reported anxiety and blood pressure were measured at baseline, post-induction, and post-intervention. Study 2 included state mindfulness as a dependent measure. RESULTS: Study 1 indicated that participants who listened to music (self-selected and researcher-selected) reported significantly greater anxiety reduction than participants in the silent control condition. Music did not reduce anxiety compared to an active control in Study 2. However, music listening significantly increased levels of state mindfulness, which predicted lower anxiety after self-selected music listening. CONCLUSIONS: Music may provide regulation in preparation for stressful events. Yet, the results of Study 2 indicate that other activities have similar benefits, and shows, for the first time, that music listening increases mindfulness following a stressor.

Self-initiated learning reveals memory performance and electrophysiological differences between younger, older and older adults with relative memory impairment.

Older adults display difficulties in encoding and retrieval of information, resulting in poorer memory. This may be due to an inability of older adults to engage elaborative encoding strategies during learning. This study examined behavioural and electrophysiological effects of explicit cues to self-initiate learning during encoding and subsequent recognition of words in younger adults (YA), older control adults (OA) and older adults with relative memory impairment (OD). The task was a variation of the old/new paradigm, some study items were preceded by a cue to learn the word (L) while others by a do not learn cue (X). Behaviourally, YA outperformed OA and OD on the recognition task, with no significant difference between OA and OD. Event-related potentials at encoding revealed enhanced early visual processing (70-140 ms) for L- versus X-words in young and old. Only YA exhibited a greater late posterior positivity (LPP; 200-500 ms) for all words during encoding perhaps reflecting superior encoding strategy. During recognition, only YA differentiated L- versus X-words with enhanced frontal P200 (150-250 ms) suggesting impaired early word selection for retrieval in older groups; however, OD had enhanced P200 activity compared to OA during L-word retrieval. The LPP (250-500 ms) was reduced in amplitude for L-words compared to both X- and new words. However, YA showed greater LPP amplitude for all words compared to OA. For older groups, we observed reduced left parietal hemispheric asymmetry apparent in YA during encoding and recognition, especially for OD. Findings are interpreted in the light of models of compensation and dedifferentiation associated with age-related changes in memory function.

Listening to self-chosen music regulates induced negative affect for both younger and older adults.

The current study evaluated the efficacy of self-chosen music listening for the function of affect regulation comparing effects in younger and older adults. Forty younger (18-30 years, M = 19.75, SD = 2.57, 14 males) and forty older (60-81 years, M = 68.48, SD = 6.07, 21 males) adults visited the laboratory and were randomised to either the intervention (10 minutes of listening to self-chosen music) or the active control condition (10 minutes of listening to an experimenter-chosen radio documentary). Negative affect (NA) was induced in all participants using a speech preparation and mental arithmetic task, followed by the intervention/control condition. Measures of self-reported affect were taken at baseline, post-induction and post-intervention. Controlling for baseline affect and reactivity to the NA induction, in comparison with the active control group the music listening group demonstrated greater reduction in NA. Supporting developmental theories of positive ageing, analyses also found significant main effects for age, with older adults experiencing greater reduction of NA than younger adults, regardless of condition. Results of the current study provide preliminary insights into the effects of self-chosen music on induced NA, however, additional experimental control conditions comparing self-chosen and experimenter-chosen music with self-chosen and experimenter-chosen active controls are needed to fully understand music listening effects for affect regulation.