Excitable systems: A new perspective on the cellular impact of elongate mineral particles.

We investigate how the geometry of elongate mineral particles (EMPs) in contact with cells influences esotaxis, a recently discovered mechanism of texture sensing. Esotaxis is based on cytoskeletal waves and oscillations that are nucleated, shaped, and steered by the texture of the surroundings. We find that all EMPs studied trigger an esotactic response in macrophages, and that this response dominates cytoskeletal activity in these immune cells. In contrast, epithelial cells show little to no esotactic response to the EMPs. These results are consistent with the distinct interactions of both cell types with ridged nanotopographies of dimensions comparable to those of asbestiform EMPs. Our findings raise the question of whether narrow, asbestiform EMPs may also dominate cytoskeletal activity in other types of immune cells that exhibit similar esotactic effects. These findings, together with prior studies of esotaxis, lead us to the hypothesis that asbestiform EMPs suppress the migration of immune cells and activate immune signaling, thereby outcompeting signals that would normally stimulate the immune system in nearby tissue.

Additive Modulation of DNA-DNA Interactions by Interstitial Ions.

Quantitative understanding of biomolecular electrostatics, particularly involving multivalent ions and highly charged surfaces, remains lacking. Ion-modulated interactions between nucleic acids provide a model system in which electrostatics plays a dominant role. Using ordered DNA arrays neutralized by spherical cobalt3+ hexammine and Mg2+ ions, we investigate how the interstitial ions modulate DNA-DNA interactions. Using methods of ion counting, osmotic stress, and x-ray diffraction, we systematically determine thermodynamic quantities, including ion chemical potentials, ion partition, DNA osmotic pressure and force, and DNA-DNA spacing. Analyses of the multidimensional data provide quantitative insights into their interdependencies. The key finding of this study is that DNA-DNA forces are observed to linearly depend on the partition of interstitial ions, suggesting the dominant role of ion-DNA coupling. Further implications are discussed in light of physical theories of electrostatic interactions and like-charge attraction.

Actin Dynamics as a Multiscale Integrator of Cellular Guidance Cues.

Migrating cells must integrate multiple, competing external guidance cues. However, it is not well understood how cells prioritize among these cues. We investigate external cue integration by monitoring the response of wave-like, actin-polymerization dynamics, the driver of cell motility, to combinations of nanotopographies and electric fields in neutrophil-like cells. The electric fields provide a global guidance cue, and approximate conditions at wound sites in vivo. The nanotopographies have dimensions similar to those of collagen fibers, and act as a local esotactic guidance cue. We find that cells prioritize guidance cues, with electric fields dominating long-term motility by introducing a unidirectional bias in the locations at which actin waves nucleate. That bias competes successfully with the wave guidance provided by the bidirectional nanotopographies.

Cortical waves mediate the cellular response to electric fields.

Electrotaxis, the directional migration of cells in a constant electric field, is important in regeneration, development, and wound healing. Electrotaxis has a slower response and a smaller dynamic range than guidance by other cues, suggesting that the mechanism of electrotaxis shares both similarities and differences with chemical-gradient-sensing pathways. We examine a mechanism centered on the excitable system consisting of cortical waves of biochemical signals coupled to cytoskeletal reorganization, which has been implicated in random cell motility. We use electro-fused giant Dictyostelium discoideum cells to decouple waves from cell motion and employ nanotopographic surfaces to limit wave dimensions and lifetimes. We demonstrate that wave propagation in these cells is guided by electric fields. The wave area and lifetime gradually increase in the first 10 min after an electric field is turned on, leading to more abundant and wider protrusions in the cell region nearest the cathode. The wave directions display 'U-turn' behavior upon field reversal, and this switch occurs more quickly on nanotopography. Our results suggest that electric fields guide cells by controlling waves of signal transduction and cytoskeletal activity, which underlie cellular protrusions. Whereas surface receptor occupancy triggers both rapid activation and slower polarization of signaling pathways, electric fields appear to act primarily on polarization, explaining why cells respond to electric fields more slowly than to other guidance cues.

Identification and comparison of key criteria of feedback of funding decisions: mixed-methods analysis of funder and applicant perspectives.

OBJECTIVE: This study investigated the content, quality and value of feedback given to applicants who applied to one of four research programmes in the UK funded (or jointly funded) by the National Institute for Health Research (NIHR). METHODS: A mixed-method phased approach was conducted using document analysis and an online survey. Phase 1 examined 114 NIHR applicant feedback documents comprised written feedback from funding committees and external peer-reviewers and a conceptual framework of the key components of feedback was developed using content analysis. Phase 2 was an online survey completed by 113 NIHR applicants. Frequencies of responses to closed questions were calculated. Perceptions of quality and value of feedback were identified using content analysis of open-text responses. RESULTS: In phase 1, a conceptual framework was developed with seven overarching categories: 'Study structure and quality'; 'Team and infrastructure'; 'Acceptability to patients and professionals'; 'Study justification and design'; 'Risks and contingencies'; 'Outputs'; 'Value for money'. A higher frequency of feedback was provided at stage 2 and for successful applications across the majority of components. In phase 2, frequency data showed that opinion on feedback was dependent on funding outcome. Content analysis revealed four main themes: 'Committee transparency'; 'Content validity and reliability'; 'Additional support'; Recognition of effort and constraints'. CONCLUSIONS: This study provides key insights and understanding into the quality, content and value of feedback provided to NIHR applicants. The study identified key areas for improvement that can arise in NIHR funding applications, as well as in the feedback given to applicants that are applicable to other funding organisations. These findings could be used to inform funding application guidance documents to help researchers strengthen their applications and used more widely by other funders to inform their feedback processes.

Decision-making approaches used by UK and international health funding organisations for allocating research funds: A survey of current practice.

Innovations in decision-making practice for allocation of funds in health research are emerging; however, it is not clear to what extent these are used. This study aims to better understand current decision-making practices for the allocation of research funding from the perspective of UK and international health funders. An online survey (active March-April 2019) was distributed by email to UK and international health and health-related funding organisations (e.g., biomedical and social), and was publicised on social media. The survey collected information about decision-making approaches for research funding allocation, and covered assessment criteria, current and past practices, and considerations for improvements or future practice. A mixed methods analysis provided descriptive statistics (frequencies and percentages of responses) and an inductive thematic framework of key experiences. Thirty-one responses were analysed, representing government-funded organisations and charities in the health sector from the UK, Europe and Australia. Four themes were extracted and provided a narrative framework. 1. The most reported decision-making approaches were external peer review, triage, and face-to-face committee meetings; 2. Key values underpinned decision-making processes. These included transparency and gaining perspectives from reviewers with different expertise (e.g., scientific, patient and public); 3. Cross-cutting challenges of the decision-making processes faced by funders included bias, burden and external limitations; 4. Evidence of variations and innovations from the most reported decision-making approaches, including proportionate peer review, number of decision-points, virtual committee meetings and sandpits (interactive workshop). Broadly similar decision-making processes were used by all funders in this survey. Findings indicated a preference for funders to adapt current decision-making processes rather than using more innovative approaches: however, there is a need for more flexibility in decision-making and support to applicants. Funders indicated the need for information and empirical evidence on innovations which would help to inform decision-making in research fund allocation.

Using digital tools in the recruitment and retention in randomised controlled trials: survey of UK Clinical Trial Units and a qualitative study.

BACKGROUND: Recruitment and retention of participants in randomised controlled trials (RCTs) is a key determinant of success but is challenging. Trialists and UK Clinical Research Collaboration (UKCRC) Clinical Trials Units (CTUs) are increasingly exploring the use of digital tools to identify, recruit and retain participants. The aim of this UK National Institute for Health Research (NIHR) study was to identify what digital tools are currently used by CTUs and understand the performance characteristics required to be judged useful. METHODS: A scoping of searches (and a survey with NIHR funding staff), a survey with all 52 UKCRC CTUs and 16 qualitative interviews were conducted with five stakeholder groups including trialists within CTUs, funders and research participants. A purposive sampling approach was used to conduct the qualitative interviews during March-June 2018. Qualitative data were analysed using a content analysis and inductive approach. RESULTS: Responses from 24 (46%) CTUs identified that database-screening tools were the most widely used digital tool for recruitment, with the majority being considered effective. The reason (and to whom) these tools were considered effective was in identifying potential participants (for both Site staff and CTU staff) and reaching recruitment target (for CTU staff/CI). Fewer retention tools were used, with short message service (SMS) or email reminders to participants being the most reported. The qualitative interviews revealed five themes across all groups: 'security and transparency'; 'inclusivity and engagement'; 'human interaction'; 'obstacles and risks'; and 'potential benefits'. There was a high level of stakeholder acceptance of the use of digital tools to support trials, despite the lack of evidence to support them over more traditional techniques. Certain differences and similarities between stakeholder groups demonstrated the complexity and challenges of using digital tools for recruiting and retaining research participants. CONCLUSIONS: Our studies identified a range of digital tools in use in recruitment and retention of RCTs, despite the lack of high-quality evidence to support their use. Understanding the type of digital tools in use to support recruitment and retention will help to inform funders and the wider research community about their value and relevance for future RCTs. Consideration of further focused digital tool reviews and primary research will help to reduce gaps in the evidence base.

Evaluation of stakeholder views on peer review of NIHR applications for funding: a qualitative study.

OBJECTIVES: Innovations resulting from research have both national and global impact, so selecting the most promising research studies to fund is crucial. Peer review of research funding applications is part of the selection process, and requires considerable resources. This study aimed to elicit stakeholder opinions about which factors contribute to and influence effective peer review of funding applications to the UK National Institute for Health Research (NIHR), and to identify possible minor improvements to current processes and any major changes or potential innovations to achieve a more efficient peer review process. DESIGN: Qualitative interviews with 30 stakeholders involved in the peer review process. PARTICIPANTS: Participants were drawn from three NIHR coordinating centres and represented four types of stakeholders: board members with responsibility for making funding decisions, applicants, external peer reviewers and NIHR staff. METHODS: All interviews were conducted by telephone apart from three that were face to face with NIHR staff. Data were analysed using a thematic template method. RESULTS: The responses from NIHR staff, board members and reviewers differed from those received from applicants. The first three groups focused on how well the process of peer review did or did not function. The applicants mentioned these points but in addition often reflected on how their personal application was assessed. Process improvements suggested included: developing a more proportionate review process; providing greater guidance, feedback, training, acknowledgement or incentives for peer reviewers; reducing the time commitment and amount of paperwork; and asking reviewers to comment on the importance, strengths and weaknesses of applications and flaws which are potentially 'fixable'. CONCLUSIONS: Overall, participants were supportive of the need for peer review in evaluating applications for research funding. This study revealed which parts of the process are working well and are valued, and barriers, difficulties and potential areas for improvement and development.