Search

Lung megakaryocytes (Mks) are largely extravascular with an immune phenotype (1). Because bone marrow (BM) Mks are short lived, it has been assumed that extravascular lung Mks are constantly 'seeded' from the BM. To investigate lung Mk origins and how origin affects their functions, we developed methods to specifically label lung Mks using CFSE dye and biotin delivered via the oropharyngeal route. Labeled lung Mks were present for up to 4 months, while BM Mks had a lifespan of less than 1 week. In a parabiosis model, lung Mks were partially replaced over 1 month from a circulating source. Unlike tissue-resident macrophages, using [MDS1.sup.-Cre-ERT2] TdTomato mice, we found that lung Mks arose from hematopoietic stem cells. However, studies with FlkSwitch mTmG mice showed that lung Mks were derived from a Flt3-independent lineage that did not go through a multipotent progenitor. CFSE labeling to track lung Mk-derived platelets showed that approximately 10% of circulating platelets were derived from lung-resident Mks at steady state, but in sterile thrombocytopenia this was doubled (~20%). Lung-derived platelets were similarly increased in a malaria infection model (Plasmodium yoelii) typified by thrombocytopenia. These studies indicate that lung Mks arise from a Flt3- BM source, are long-lived, and contribute more platelets during thrombocytopenia., Introduction Platelets serve dual roles as a critical component of clot formation and as regulators of immune responses (1, 2). Activated platelets promote inflammation, while circulating resting platelets limit inflammation [...]

Summary: Motivation: Multi‐stakeholder dialogues (MSDs) are a popular tool to promote good governance in the global south, but it remains unclear whether they actually bring about the deeper benefits they are designed to achieve, namely better government responsiveness and higher public confidence in political institutions. Niger is one of the least developed countries in the world and one where citizens consistently report low confidence in government. Purpose: We test the impact of MSDs on government responsiveness and public confidence in political institutions in Niger. Specifically, we test whether MSDs in communes focused on education and health improve relations between citizens and leaders, make processes more representative, and increase resources for local service delivery. We test whether MSDs improve citizen perceptions of government: legitimacy, responsiveness, democracy, and honesty. We test whether they increase citizen participation, including through petitions and messaging. Methods and approach: Randomized controlled trial and surveys. Findings: MSDs had virtually no positive impact on any of the 10 tests we conducted, with no appreciable improvements in local political leadership or in citizen engagement with, and confidence in, the state and its services. The null results may arise from the limited time the MSDs were run, or they may reflect the extremely difficult conditions for better local governance seen in Niger. Policy implications: The findings, though possibly discouraging for policy implementers, provide a valuable opportunity to contemplate how multi‐stakeholder frameworks might be made more effective and whether to prioritize alternative frameworks for democracy and development in countries like Niger. MSDs may be worth continuing in combination with other interventions, or simply in the interest of an inclusive, ethical approach to development. [ABSTRACT FROM AUTHOR]

Satisfactory healing following acute tendon injury is marred by fibrosis. Despite the high frequency of tendon injuries and poor outcomes, there are no pharmacological therapies in use to enhance the healing process. Moreover, systemic treatments demonstrate poor tendon homing, limiting the beneficial effects of potential tendon therapeutics. To address this unmet need, we leveraged our existing tendon healing spatial transcriptomics dataset and identified an area enriched for expression of Acp5 (TRAP) and subsequently demonstrated robust TRAP activity in the healing tendon. This unexpected finding allowed us to refine and apply our existing TRAP binding peptide (TBP) functionalized nanoparticle (NP) drug delivery system (DDS) to facilitate improved delivery of systemic treatments to the healing tendon. To demonstrate the translational potential of this DDS, we delivered niclosamide (NEN), an S100a4 inhibitor. While systemic delivery of free NEN did not alter healing, TBP-NPNEN enhanced both functional and mechanical recovery, demonstrating the translational potential of this approach to enhance the tendon healing process. [ABSTRACT FROM AUTHOR]