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Improved wound healing by dual inhibition of miR-146a-5p and miR-29a-3p supports a network action of dysregulated miRNAs in diabetic skin
No full textAims/hypothesis Upregulation of miR-146a-5p and miR-29-3p is observed in chronic non-healing wounds in diabetes.Their single or combined inhibition's molecular and cellular effects were assessed in human keratinocytes (HaCaT cells)and in vivo using a mouse model of type 1 diabetes.Methods As primary outcomes, we screened for proteome changes in HaCaT cells by LC-MS/MS after transfection withmiR-146a-5p or miR-29a-3p inhibitors individually or in combination and following stimulation with TNF-α. Moreover, asa secondary outcome, we collected the data and cryopreserved and paraffin-embedded skin biopsies to estimate the tissueresponse to miRNA inhibition using immunofluorescence and histological analysis. Cryopreserved biopsies were also usedfor the LC-MS/MS proteome profiling to identify targets and cellular pathways involved in observed tissue changes.Results We identified a panel of extracellular matrix proteins, mainly laminins, whose levels changed after transfectionwith miR-146a-5p or miR-29a-3p inhibitors in HaCaT cells, counteracting TNF-α effects. There was a difference in woundclosure rate in vivo between the dual inhibition of miR-146a-5p and miR-29a-3p and scramble controls on day 8 (p<0.01)and day 9 (p<0.05), although not at day 10. Histological analysis at day 10 shows a loose papillary layer in the scrambleinhibition group, indicating incomplete wound closure compared with dual miRNA inhibition. Moreover, the dual action ofthe inhibitors decreased inflammation at day 3 and day 10 (both p<0.001) and reactive oxygen species formation (p<0.01)3 days post wounding, while increasing the angiogenesis on day 3 (p<0.01) and day 10 (p<0.001). This was consistent withcytoskeletal rearrangements and collagen alterations observed in proteome profiling.Conclusions/interpretationThese findings demonstrate that dual inhibition of miR-146a-5p and miR-29a-3p in vitro syner-gises in a bidirectional manner, resulting either in intermediate effects or in cancelling each other’s activity for the levels ofspecific proteins of basal lamina that impair proliferation and cell motility, compared with the individual inhibitors. Topicalsupplementation of miR-146a-5p and miR-29a-3p inhibitors to diabetic mouse wounds resulted in a reduction in wound sizeon days 8 and 9, which correspond to the later stages of healing, but did not lead to complete healing by day 10. However,dual inhibition demonstrates favourable effects on high oxidative stress, elevated inflammation and poor angiogenesis. Theseeffects are superior to single miRNA inhibition, suggesting that combined miRNA inhibition could be a promising therapeuticstrategy for diabetic wound healing. Nevertheless, further studies in humans are warranted.Aims/hypothesis: Upregulation of miR-146a-5p and miR-29-3p is observed in chronic non-healing wounds in diabetes. Their single or combined inhibition's molecular and cellular effects were assessed in human keratinocytes (HaCaT cells) and in vivo using a mouse model of type 1 diabetes. Methods: As primary outcomes, we screened for proteome changes in HaCaT cells by LC-MS/MS after transfection with miR-146a-5p or miR-29a-3p inhibitors individually or in combination and following stimulation with TNF-α. Moreover, as a secondary outcome, we collected the data and cryopreserved and paraffin-embedded skin biopsies to estimate the tissue response to miRNA inhibition using immunofluorescence and histological analysis. Cryopreserved biopsies were also used for the LC-MS/MS proteome profiling to identify targets and cellular pathways involved in observed tissue changes. Results: We identified a panel of extracellular matrix proteins, mainly laminins, whose levels changed after transfection with miR-146a-5p or miR-29a-3p inhibitors in HaCaT cells, counteracting TNF-α effects. There was a difference in wound closure rate in vivo between the dual inhibition of miR-146a-5p and miR-29a-3p and scramble controls on day 8 (p<0.01) and day 9 (p<0.05), although not at day 10. Histological analysis at day 10 shows a loose papillary layer in the scramble inhibition group, indicating incomplete wound closure compared with dual miRNA inhibition. Moreover, the dual action of the inhibitors decreased inflammation at day 3 and day 10 (both p<0.001) and reactive oxygen species formation (p<0.01) 3 days post wounding, while increasing the angiogenesis on day 3 (p<0.01) and day 10 (p<0.001). This was consistent with cytoskeletal rearrangements and collagen alterations observed in proteome profiling. Conclusions/interpretation: These findings demonstrate that dual inhibition of miR-146a-5p and miR-29a-3p in vitro synergises in a bidirectional manner, resulting either in intermediate effects or in cancelling each other’s activity for the levels of specific proteins of basal lamina that impair proliferation and cell motility, compared with the individual inhibitors. Topical supplementation of miR-146a-5p and miR-29a-3p inhibitors to diabetic mouse wounds resulted in a reduction in wound size on days 8 and 9, which correspond to the later stages of healing, but did not lead to complete healing by day 10. However, dual inhibition demonstrates favourable effects on high oxidative stress, elevated inflammation and poor angiogenesis. These effects are superior to single miRNA inhibition, suggesting that combined miRNA inhibition could be a promising therapeutic strategy for diabetic wound healing. Nevertheless, further studies in humans are warranted.</p
The <i>JAK2V617F</i> and <i>CALR</i> mutations and risk of cancer, cardiovascular diseases, and all-cause mortality
Full text linkBackground: Clonal hematopoiesis (CH) is associated with adverse outcomes. We hypothesized that CH (JAK2V617F and CALR) is associated with cancer, vascular disease, and all-cause mortality, even at a variant allele frequency (VAF) <1%.Methods: We screened 19,832 individuals from the Danish General Suburban Population Study for JAK2V617F and CALR mutations by digital-droplet PCR. We used Cox regression with hazard ratio (HR) and 95% confidence interval (95%CI), stratified by CH (JAK2V617F and CALR), VAF (<1% vs. ≥1%), mutation type (JAK2V617F or CALR), and JAK2V617F VAF.Results: The HR (95%CI) for any cancer was 1.71 (1.46-2.01) in CH, 1.28 (1.05-1.56) in VAF < 1%, 4.35 (3.34-5.66) in VAF ≥ 1%, and higher for JAK2V617F but not CALR. For hematological cancer, the HR (95%CI) was 8.41 (6.44-10.99) in CH, 3.53 (2.35-5.30) in VAF < 1%, and 40.01 (28.97-55.26) in VAF ≥ 1%, and also higher for JAK2V617F and CALR. For arterial diseases, the HR (95%CI) was 1.25 (1.03-1.52) in CH, 1.75 (1.18-2.59) in VAF ≥ 1%, and 1.28 (1.05-1.55) in JAK2V617F. The HR for venous disease was only higher in JAK2V617F VAF ≥ 1%. The HR (95%CI) for all-cause mortality was 1.45 (1.19-1.75) in CH, 1.36 (1.10-1.69) in VAF < 1%, 1.91 (1.26-2.88) in VAF ≥ 1%, and also higher for JAK2V617F and CALR. The population-attributable risk proportion (95%CI) for myeloproliferative neoplasms (MPNs) was 76.6% (66.8-86.4) in CH, 47.1% (29.6-64.6) in VAF < 1%, and 71.0% (59.4-82.6) in VAF ≥ 1%, with a nomogram generated.Conclusions: CH-defined by the JAK2V617F and CALR mutations-was associated with cancer, MPN, all-cause mortality-even with VAF < 1%-and vascular diseases at VAF ≥ 1%. These are novel findings, indicating that the JAK2V617F and CALR mutations confer an oncogenic potential with a VAF below the current CH of indeterminate potential definition
Exploring the Potential of Telepresence Robots for Individuals Living Abroad and Their Families:A Qualitative Approach
No full textThe emergence of telepresence robots (TPRs) as mobile tools that can enable remote presence and interaction has been the focus of many endeavors that have provided insights on TPRs’ application in research, educational contexts, professional training, social inclusion and sense of embodiment. In this paper we have conducted semi-structured interviews with five individuals living abroad and one family member of a person living abroad to explore how TPRs can be employed to strengthen family ties and enhance the sense of presence in order to alleviate the emotional struggle that is often reported in these groups. Based on the participants’ responses we have showcased the relation between different technological features and communication, addressed concerns regarding the use of TPRs, and recognized activities that can be recreated remotely with the use of a TPR to potentially create an enhanced feeling of connection. The analysis presented could be the premise for subsequent implementation of TPRs in a way that is considered meaningful by people living in distance from their families
A Tableau System for First-Order Logic with Standard Names
No full textLevesque and Lakemeyer proposed a logic called L as a first-order logic for knowledge representation and reasoning in knowledge-based systems. A characteristic feature of this logic is that it uses a countably infinite set of what are called standard names, which are syntactically treated like constants, but which are also isomorphic to a fixed universe of discourse. Quantifiers in L are then given a substitutional interpretation. This non-standard semantics not only simplifies the proofs for certain meta-theoretic properties, but is also exploited in dedicated reasoning procedures for modal extensions of L that include notions of belief, actions, time, and more. However, the only sound and complete proof system provided for L so far is a Hilbert-style axiom system, as well as an iterative reasoning mechanism based on resolution and clause subsumption. In this paper, we present a tableau system for L, and show its soundness and completeness. Completeness is proved first by reduction to the existing axiom system, and involves the cut rule, and then via Hintikka sets, which does not require the cut rule
From Data to AI-based Discovery:The Maken project at the National Library of Norway
No full textAbstract This chapter provides an overview of the National Library of Norway as well as an overview of the AI initiatives taking place at the library. The chap-ter presents details of a specific AI project, Maken. Maken is a discovery engine that finds similar books and images. For example, based on the pixels of a given image, Maken finds related images or based on the text of a book, Maken finds similar books. The chapter provides insights into the needs for developing Maken, the actors involved in the project implementation and the challenges en-countered. Finally, the chapter provides some insights into the value that such a project generates for different stakeholders, the lessons learned in the implemen-tation phase and the skills that the library needs to adopt AI.This chapter provides an overview of the National Library of Norway as well as an overview of the AI initiatives taking place at the library. The chapter presents details of a specific AI project, Maken. Maken is a discovery engine that finds similar books and images. For example, based on the pixels of a given image, Maken finds related images, or based on the text of a book, Maken finds similar books. The chapter provides insights into the needs for developing Maken, the actors involved in the project implementation and the challenges encountered. Finally, the chapter provides some insights into the value that such a project generates for different stakeholders, the lessons learned in the implementation phase and the skills that the library needs to adopt AI
The disenchanted fairy godmother:Comparing how and why evidence-based management and public service professionals influenced policy performance in public school and active labour market policy in Denmark
No full textBackground:The aspiration to use evidence to enhance the legitimacy and effectiveness of policies is widely shared but often falls short. A common explanation for failure is the presence of barriers to utilising evidence or the inadequacies of the evidence available to policy makers.Aims and objectives:The article examines how and why evidence-based policies sometimes fail to enhance policy performance, through a comparative analysis of evidence-based management in Danish public school and active labour market policies after 2000. The two cases are characterised by similar policy performance problems but vary in terms of evidence-based management styles and responses from public service professionals.Methods:The article relies on document analysis and expert interviews with civil servants and key stakeholders to explain how and why evidence-based policies fail to improve policy performance in the two cases.Findings:We find that evidence-based policy making did not resolve performance problems in either case, though for different reasons. In public school policy, conflict over the 2014 Public School Reform impacted negatively on its implementation despite efforts to incorporate evidence in its design. In active labour market policy, evidence-based policies were imposed on job centres and institutionalised in key performance indicators, but over time critique of processual requirements and indignified casework accumulated and contributed towards a political decision to reform job centres.Discussion and conclusion:We advocate for setting realistic expectations about the potential of evidence in resolving policy performance problems and caution against overstating the ‘dream’ of evidence-based policy making
Theoretical Framing of Public Administration Research
No full textThis article presents and discusses a heuristic meta-theoretical framework for PA research. There are often theories implicit in research, but what is described as theory is too often merely a set of hypotheses derived from previous research that also lacked proper theoretical grounding. We argue that more explicit attention to theory will make public administration research more cumulative and link it more directly to other disciplines. Our heuristic theoretical framework enables researchers to select and combine key theoretical building blocks and make informed choice of the theoretical perspective, thus assembling a purpose-built theoretical framework capable of guiding empirical research
Ethics and Professional Identity in Welfare work:A socio-material and psycho-societal approach
No full textDenne bogs samlede tema er etik i velfærdsprofessionelt arbejde. Begrebet etik er filosofisk og betegner overvejelser over tilstræbelsesværdige handlinger og konkrete forskrifter for hvordan man skal forholde sig til andre mennesker, med relevans for individuelle handlinger og relationer. Det forekommer indlysende at konkret professionelt arbejde giver anledning til denne type overvejelser. Professionelt arbejde er arbejde med konsekvenser for andre mennesker og et ansvar for arbejdets faglige kvalitet. Bestræbelsen er derfor at udvikle en materialistisk forståelse af etiske spørgsmål ved at betragte dem som dimensioner i professionelt arbejde snarere end som udefra begrundede forskrifter for det. Teoretisk og metodologisk anlægges en psyko-social begrebslig ramme som gør det muligt at undersøge hvilke etiske overvejelser der faktisk er er til stede i det professionelle velfærdsarbejde, hvoraf de kommer, og hvilken betydning de har for arbejdets retning og kvalitet. For at forstå oprindelsen til konkrete praktikeres tanker og følelser om deres arbejde må vi anskue disse orienteringer i forhold til deres livshistoriske erfaringer og i forhold de samfundsmæssige og historiske rammer for arbejdet
Applying AI to increase cultural accessibility:The postcard project at the Royal Danish Library
No full textThis chapter provides an overview of the Danish Royal Library as well as an overview of AI adoption and implementation initiatives taking place at the library. Finally, the chapter presents details of a specific AI project, the postcard project. The Post Card Project comprises the digitalisation of the postcard collection of Danish Royal Library. It includes the digitalisation of approx. 350,000 topographical postcards from the period 1887 to the 1990s from all parts of Denmark and making them accessible to the broader public by using AI. The chapter provides insights into the needs of the project, the actors involved in the implementation and the challenges encountered on the way. Finally, the chapter provides insights into the value that such a project generates for different stakeholders, as well as the lessons learned in the implementation phase.This chapter provides an overview of the Danish Royal Library as well as an overview of AI adoption and implementation initiatives taking place at the library. Finally, the chapter presents details of a specific AI project, the postcard project. The Postcard project comprises the digitalisation of the postcard collection of the Danish Royal Library. It includes the digitalisation of approx. 350,000 topographical postcards from the period 1887 to the 1990s from all parts of Denmark and making them accessible to the broader public by using AI. The chapter provides insights into the needs of the project, the actors involved in the implementation and the challenges encountered on the way. Finally, the chapter provides insights into the value that such a project generates for different stakeholders, as well as the lessons learned in the implementation phase
Design and characterization of antibiotic-free lyotropic liquid crystalline coatings based on binary docosahexaenoic acid monoglyceride/glycerol monooleate systems for combating orthopedic implant-associated infections
Full text linkThere is a growing interest in innovative strategies for effectively preventing implant-associated bacterial infections. Here, we report on a simple-by-design approach for production of antibacterial coatings from docosahexaenoic acid monoacylglycerol (MAG-DHA) and glycerol monooleate (GMO). In addition to its amphiphilic nature, MAG-DHA is a safe precursor of docosahexaenoic acid (DHA) and has different beneficial health effects, including antibacterial activities. Using binary combinations of MAG-DHA and GMO, we describe the structural features and the antibacterial activities of antibiotic-free non-lamellar liquid crystalline (LLC) coatings. Small-angle X-ray scattering (SAXS) and in situ grazing incidence small-angle X-ray scattering (GISAXS) were employed to gain insight into the structural features of the fully hydrated coatings and the hydration-induced dynamic self-assembly of MAG-DHA and GMO on model implants. In a lipid composition-dependent manner, SAXS results revealed hydration-induced formation of different inverse LLC self-assemblies, including hexagonal (H2) and bicontinuous cubic (Q2) phases. Further, GISAXS analysis showed that lipid composition and employed relative humidity level play important roles in controlling the out-of-equilibrium self-assembly properties. Moreover, the coatings containing MAG-DHA displayed unique inherent antibacterial activities against Staphylococcus aureus and Staphylococcus epidermidis strains. This study describes the first antibiotic-free coatings with nanostructural architectures and inherent antibacterial activities for orthopedic implants.</p