Designing and implementing a research integrity promotion plan: Recommendations for research funders

Various stakeholders in science have put research integrity high on their agenda. Among them, research funders are prominently placed to foster research integrity by requiring that the organizations and individual researchers they support make an explicit commitment to research integrity. Moreover, funders need to adopt appropriate research integrity practices themselves. To facilitate this, we recommend that funders develop and implement a Research Integrity Promotion Plan (RIPP). This Consensus View offers a range of examples of how funders are already promoting research integrity, distills 6 core topics that funders should cover in a RIPP, and provides guidelines on how to develop and implement a RIPP. We believe that the 6 core topics we put forward will guide funders towards strengthening research integrity policy in their organization and guide the researchers and research organizations they fund.

Research funders are prominently placed to foster research integrity by requiring that researchers make an explicit commitment to research integrity. This Consensus View suggests 6 core topics that funders should cover in a research integrity promotion plan and provides practical recommendations for how to implement one.

To improve research quality and validity, foster responsible research cultures, and maintain public trust in science, various stakeholders have put research integrity high on their agenda. Among them, research funders are increasingly acknowledging their pivotal role in contributing to a culture of research integrity. For example, the European Commission (EC) is mandating research organizations receiving funding from the €95 billion Horizon Europe program to have, at the institutional level, policies and processes in place for research integrity covering the promotion of good practice, prevention of misconduct and questionable practices, and procedures to deal with breaches of research integrity [1]. To meet these obligations, the EC requires beneficiaries to respect the principles of research integrity as set out in the European Code of Conduct for Research Integrity (ECoC) and suggests that research organizations develop and implement a Research Integrity Promotion Plan (RIPP) [2]. In this Consensus View, we have adopted the World Conference on Research Integrity’s approach to research integrity, by having “research integrity” refer to “the principles and standards that have the purpose to ensure validity and trustworthiness of research” [3]. More specifically, we mostly adhere to the principles outlined in the ECoC: reliability, honesty, respect, and accountability. While many definitions of research integrity exist [4,5], for example, those that distinguish between the integrity of a researcher, integrity of research, and integrity of the research record, the ECoC combines these approaches in a balanced way [1].We believe that funders are prominently placed to foster a culture of research integrity by requiring that the organizations and individual researchers they support make an explicit commitment to research integrity. At the same time, funders need to adopt appropriate research integrity practices themselves. Of late, attention to research integrity among funders has gathered pace, as reflected in several initiatives around the globe that demonstrate how funders can support a culture of research integrity. For example, the US National Science Foundation (NSF) [6] requires applicants’ research organizations to provide training and oversight in the responsible conduct of research, designate individuals responsible for research integrity, and have an institutional certification to testify of its commitment. Also, in 2016, 3 Canadian federal funders joined forces to support research integrity in the Canadian Tri-Agency Framework: Responsible Conduct of Research–Harmony and Responsibility [7]. The framework was subsequently updated in 2021. This framework sets out responsible practices that research organizations and researchers should follow, including rigor, record keeping, accurate referencing, responsible authorship, and the management of conflicts of interest. It also acknowledges the responsibilities of the funders, including “helping to promote the responsible conduct of research and to assist individuals and institutions with the interpretation or implementation of this Responsible Conduct of Research (RCR) Framework”.It is not only major funding organizations in highly developed research environments that are taking steps. Smaller funders are also acting to mandate compliance with research integrity standards. The constantly growing literature on the topic is another sign of development within this area [2,3]. In the USA, research integrity recently reached the political arena, when, following a call from researchers [8], President Biden’s administration published a memorandum on restoring trust [9] that highlights the importance of integrity in research. The memorandum will be supported by the reintroduction of the Scientific Integrity Act. This act will prohibit research misconduct and the manipulation of research findings. It talks of a “culture of research integrity” and demands that funding agencies adopt and enforce research integrity policies, appoint a research integrity officer, and provide regular research integrity and ethics training. The US are not alone in their endeavors. Governments in other countries are equally gearing up to support the integrity and reproducibility of research [10]. However, so far, there is only limited evidence about the effectiveness of such initiatives, although it is generally accepted that they raise awareness among various stakeholders concerning research integrity challenges, strengthen the sense of responsibility of those stakeholders to address those challenges, and thereby ultimately contribute to fostering a culture of research integrity.In a collective effort to foster research integrity, research organizations and funders have their own, complementary roles. The Standard Operating Procedures for Research Integrity (SOPs4RI) consortium has recommended that both research organizations and funders develop a RIPP. A RIPP outlines the key responsibilities of an organization concerning research integrity and details methods and procedures to foster it. For example, in the case of research organizations, a RIPP should facilitate and stimulate a healthy research environment, proper mentoring and supervision, research ethics structures, research integrity training, high-quality dissemination practices, research collaboration, effective data management, and open and fair procedures to deal with breaches of research integrity [11]. Funders have a different role. They can support, safeguard, and incentivise, or even mandate, responsible research practices from research organizations and researchers. Equally important, funders should make sure that their internal processes live up to the highest standards of research integrity. We recognize that funders are many and varied in their scale, portfolio, disciplinary focus, and the extent to which they have procedures and governance arrangements to support research integrity. For all funders, adopting a RIPP will structure and coordinate research integrity practices, giving clarity and transparency to applicant institutions and researchers.In this Consensus View, we highlight examples of best practice of funders worldwide to foster a research integrity culture. With these examples in mind, we suggest guidelines to support funders in taking a leading role in fostering research integrity. In so doing, we acknowledge the local contexts in which funders operate, but we believe that all funders, large and small, in all parts of the world, can and should contribute to improving research validity and building and maintaining trust in science through incentivising and mandating a culture of research integrity. Our core argument is that developing a tailored RIPP will contribute to building an institutional culture of research integrity, both within funding organizations and among the research organizations and individual researchers they fund. Based on empirical work from the SOPs4RI project, we have identified 6 key research integrity topics: researchers’ compliance with research integrity standards; expectations for research organizations; selection of grant applications; declaration of interests; monitoring funded research; and dealing with internal integrity breaches (Fig 1). We recommend that these topics should be included in a RIPP and provide guidelines on developing and implementing a RIPP.Open in a separate windowFig 1Topics to be covered in a RIPP for funders.An overview of the 6 most important topics identified by the SOPs4RI to be included in research funding organization’s RIPP. RIPP, Research Integrity Promotion Plan; SOPs4RI, Standard Operating Procedures for Research Integrity.     

Interactions of neural glycosaminoglycans and proteoglycans with protein ligands: assessment of selectivity, heterogeneity and the participation of core proteins in binding

The method of affinity coelectrophoresis was used to study the binding of nine representative glycosaminoglycan (GAG)-binding proteins, all thought to play roles in nervous system development, to GAGs and proteoglycans isolated from developing rat brain. Binding to heparin and non-neural heparan and chondroitin sulfates was also measured. All nine proteins-laminin-1, fibronectin, thrombospondin-1, NCAM, L1, protease nexin-1, urokinase plasminogen activator, thrombin, and fibroblast growth factor-2-bound brain heparan sulfate less strongly than heparin, but the degree of difference in affinity varied considerably. Protease nexin-1 bound brain heparan sulfate only 1.8- fold less tightly than heparin (Kdvalues of 35 vs. 20 nM, respectively), whereas NCAM and L1 bound heparin well (Kd approximately 140 nM) but failed to bind detectably to brain heparan sulfate (Kd>3 microM). Four proteins bound brain chondroitin sulfate, with affinities equal to or a few fold stronger than the same proteins displayed toward cartilage chondroitin sulfate. Overall, the highest affinities were observed with intact heparan sulfate proteoglycans: laminin-1's affinities for the proteoglycans cerebroglycan (glypican-2), glypican-1 and syndecan-3 were 300- to 1800-fold stronger than its affinity for brain heparan sulfate. In contrast, the affinities of fibroblast growth factor-2 for cerebroglycan and for brain heparan sulfate were similar. Interestingly, partial proteolysis of cerebroglycan resulted in a >400- fold loss of laminin affinity. These data support the views that (1) GAG-binding proteins can be differentially sensitive to variations in GAG structure, and (2) core proteins can have dramatic, ligand-specific influences on protein-proteoglycan interactions.      

Low Resolution Solution Structure of HAMLET and the Importance of Its Alpha-Domains in Tumoricidal Activity

HAMLET (Human Alpha-lactalbumin Made LEthal to Tumor cells) is the first member in a new family of protein-lipid complexes with broad tumoricidal activity. Elucidating the molecular structure and the domains crucial for HAMLET formation is fundamental for understanding its tumoricidal function. Here we present the low-resolution solution structure of the complex of oleic acid bound HAMLET, derived from small angle X-ray scattering data. HAMLET shows a two-domain conformation with a large globular domain and an extended part of about 2.22 nm in length and 1.29 nm width. The structure has been superimposed into the related crystallographic structure of human α-lactalbumin, revealing that the major part of α-lactalbumin accommodates well in the shape of HAMLET. However, the C-terminal residues from L105 to L123 of the crystal structure of the human α-lactalbumin do not fit well into the HAMLET structure, resulting in an extended conformation in HAMLET, proposed to be required to form the tumoricidal active HAMLET complex with oleic acid. Consistent with this low resolution structure, we identified biologically active peptide epitopes in the globular as well as the extended domains of HAMLET. Peptides covering the alpha1 and alpha2 domains of the protein triggered rapid ion fluxes in the presence of sodium oleate and were internalized by tumor cells, causing rapid and sustained changes in cell morphology. The alpha peptide-oleate bound forms also triggered tumor cell death with comparable efficiency as HAMLET. In addition, shorter peptides corresponding to those domains are biologically active. These findings provide novel insights into the structural prerequisites for the dramatic effects of HAMLET on tumor cells.     

Life history predicts advancement of avian spring migration in response to climate change

An increasing number of studies demonstrate that plant and animal phenologies such as the timing of bird migration have been advancing over the globe, likely as a result of climate change. Even closely related species differ in their phenological responses, and the sources of this variation are poorly established. We used a large, standardized dataset of first arrival dates (FAD) of migratory birds to test the effects of phylogenetic relationships and various life-history and ecological traits on the degree to which different species adapt to climate change by earlier migration in spring. Using the phylogenetic comparative method, we found that the advancement of FAD was greater in species with more generalized diet, shorter migration distance, more broods per year, and less extensive prebreeding molt. In turn, we found little evidence that FAD trends were influenced by competition for mating (polygamy or extra-pair paternity) and breeding opportunities (cavity nests). Our findings were robust to several potentially confounding effects. These evolutionary correlations, coupled with the low levels of phylogenetic dependence we found, indicate that avian migration phenology adapts to climate change as a species-specific response. Our results suggest that the degree of this response is fundamentally shaped by constraints and selection pressures of the species' life history, and less so by the intensity of sexual selection.     

Contrasting population structure from nuclear intron sequences and mtDNA of humpback whales

Powerful analyses of population structure require information from multiple genetic loci. To help develop a molecular toolbox for obtaining this information, we have designed universal oligonucleotide primers that span conserved intron-exon junctions in a wide variety of animal phyla. We test the utility of exon-primed, intron-crossing amplifications by analyzing the variability of actin intron sequences from humpback, blue, and bowhead whales and comparing the results with mitochondrial DNA (mtDNA) haplotype data. Humpback actin introns fall into two major clades that exist in different frequencies in different oceanic populations. It is surprising that Hawaii and California populations, which are very distinct in mtDNAs, are similar in actin intron alleles. This discrepancy between mtDNA and nuclear DNA results may be due either to differences in genetic drift in mitochondrial and nuclear genes or to preferential movement of males, which do not transmit mtDNA to offspring, between separate breeding grounds. Opposing mtDNA and nuclear DNA results can help clarify otherwise hidden patterns of structure in natural populations.      

Early detection of gastric cancer.

OBJECTIVE--To see whether investigation of dyspeptic patients aged over 40 after their first consultation with the general practitioner would increase the proportions with early and operable gastric cancers. DESIGN--Prospective study of gastric cancer in dyspeptic patients aged over 40 from a defined population. SETTING--10 General practices (six in central Birmingham, four in Sandwell); the Queen Elizabeth Hospital, Birmingham; and Sandwell District General Hospital. PATIENTS--2659 Patients aged 40 or over referred with dyspepsia. MAIN OUTCOME MEASURE--Increase in early and operable gastric cancers detected in middle aged patients with dyspepsia. RESULTS--Disease was identified in 1992 patients (75%). Fifty seven were found to have gastric cancer, 36 being treated by potentially curative resection, including 15 with early cancer. CONCLUSIONS--The investigation of dyspeptic patients over 40 at first attendance can increase the proportion of early gastric cancers detected to 26% and the proportion of operable cases to 63%. Such a policy has the potential to reduce mortality from gastric cancer in the population.     

Tube-Like Structures with Co-Expression of D2-40 and CD34: Newly Formed Vasculatures?

Background: A great number of in vitro and in vivo studies have suggested that many pathways or factors can stimulate angiogenesis and lymphangiogenesis, which facilitate tumor progression and metastasis. However, the morphological and immunohistochemical profile of newly formed vasculatures has not been elucidated, making it difficult to differentiate them from the pre-existing ones, and to identify their unique molecular profiles for diagnosis and therapeutic interventions.Experimental findings: As cytokeratin (CK)-19 is a well-recognized stem cell marker and CK-19-positive cells are frequently detected in the peripheral blood of patients with metastatic cancer, our recent studies have assessed the involvement of CK-19 in the formation of new vasculatures in primary colorectal cancer (CRC) tissues. Our studies showed that a subset of lymph node-positive cases harbored some isolated normal epithelial structures with distinct CK-19 immunostaining within an otherwise CK-19-negative background. These structures are exclusively located within or adjacent to lymphoid follicles and are often surrounded by tube-like structures expressing lymphatic endothelial marker D2-40. Similar structures are more frequently seen at the junctions between pre-invasive and invasive CRC with the following features: (1). they consist of a single layer of endothelial cells that express both D2-40 and CD34, (2). their endothelial walls are often incomplete with disseminated cells protruding into the adjacent stroma, and (3). they are exclusively associated with disseminated CK-19-positive cellsHypothesis: Based on these findings, we propose that these tube-like structures represent newly formed vasculatures, which are derived by the convergence of aberrant lymphocyte infiltration and tumor stem cells. Because of their close physical proximity, tumor stem cells within the epithelial and stromal components contribute equally and coordinately to the morphogenesis of new vasculatures, which constitutes the basis for the unique morphologic and immunohistochemical features of newly formed vasculatures. Our hypothesis appears to be applicable to all epithelium-derived cancers.     

In vivo studies on the uptake of radiolabelled antibodies by colorectal and gastric carcinoma xenografts

Summary Subjection of EL-4-leukemia cells to hydrostatic pressure of 1200–1500 atm for 15 min increased their weak basal immunogenicity to a potent practical level. Injection of such pressure-treated and irradiated EL-4 cells into syngeneic naive C57Bl/6 mice significantly delayed tumor development and increased survival after subsequent challenge with untreated EL-4 cells. Application of pressure of 1500 atm for a longer period of time (e.g., 120 min) resulted in cell death and a smaller increase in tumor immunogenicity which could be partially accounted for by passive shedding of membrane material. Unlike previously studied tumor cells, incorporation of cholesteryl hemisuccinate (CHS) into the plasma membrane of EL-4 cells increased their apparent tumor immunogenicity only slightly. In addition, isolated EL-4 plasma membranes, untreated, CHS-treated or pressure-treated, as well as the material shed thereof by hydrostatic pressure, were all of weak immunogenicity.Modulation in the projection of surface antigens upon pressure treatment could account for the observed increase in tumor immunogenicity and was monitored via the Thy 1.2 antigen. Fluorescence cell sorting analysis indicated that upon application of 1500 atm for different periods of time the projection of Thy 1.2 progressively and irreversibly increased to a maximal level of about 140% at 15 min. At longer pressurizations the availability of Thy 1.2 to antibody binding decreased sharply to levels below that of the untreated cells. It is suggested that pressure promotion of tumor immunogenicity is induced by changes in projection and surface distribution of the relevant antigens.Supported by a grant from the Institut National de lo Sante et de la Recherche Medicale FRANCE.     

Inhibitory effects of some esters of 2- and 3-substituted alkoxyphenylcarbamic acids on photosynthetic characteristics

The inhibitory effect of 23N-alkyl-4-piperidylesters (alkyl = ethyl-butyl) (APEA) and 8N-ethyl-2-pyrrolidinylmethylesters (EPMEA) of 2- and 3-substituted alkoxyphenylcarbamic acids (alkoxy = butoxy-heptyloxy-) on photosynthetic Hill reaction activity of spinach chloroplasts and on chlorophyll (Chl) synthesis in green algaeChlorella vulgaris was investigated. Inhibitory activities of these compounds were strongly connected with the lipophilicity of the whole molecule. A lower inhibitory activity of 2-alkoxy-substituted derivatives in relation to the corresponding 3-substituted ones was confirmed. Electron spin resonance (ESR) spectra of spinach chloroplasts demonstrated that the studied compounds affected the structure of photosystem (PS) 2 with the release of Mn²⁺ ions into interior of thylakoid membranes.