Notch signaling enhances bone regeneration in the zebrafish mandible.

Loss or damage to the mandible caused by trauma, treatment of oral malignancies, and other diseases is treated using bone-grafting techniques that suffer from numerous shortcomings and contraindications. Zebrafish naturally heal large injuries to mandibular bone, offering an opportunity to understand how to boost intrinsic healing potential. Using a novel her6:mCherry Notch reporter, we show that canonical Notch signaling is induced during the initial stages of cartilage callus formation in both mesenchymal cells and chondrocytes following surgical mandibulectomy. We also show that modulation of Notch signaling during the initial post-operative period results in lasting changes to regenerate bone quantity one month later. Pharmacological inhibition of Notch signaling reduces the size of the cartilage callus and delays its conversion into bone, resulting in non-union. Conversely, conditional transgenic activation of Notch signaling accelerates conversion of the cartilage callus into bone, improving bone healing. Given the conserved functions of this pathway in bone repair across vertebrates, we propose that targeted activation of Notch signaling during the early phases of bone healing in mammals may both augment the size of the initial callus and boost its ossification into reparative bone.

How much donor financing for health is channelled to global versus country-specific aid functions?

The slow global response to the Ebola crisis in west Africa suggests that important gaps exist in donor financing for key global functions, such as support for health research and development for diseases of poverty and strengthening of outbreak preparedness. In this Health Policy, we use the International Development Statistics databases to quantify donor support for such functions. We classify donor funding for health into aid for global functions (provision of global public goods, management of cross-border externalities, and fostering of leadership and stewardship) versus country-specific aid. We use a new measure of donor funding that combines official development assistance (ODA) for health with additional donor spending on research and development (R&D) for diseases of poverty. Much R&D spending falls outside ODA--ie, the assistance that is conventionally reported through ODA databases of the Organisation for Economic Co-operation and Development. This expanded definition, which we term health ODA plus, provides a more comprehensive picture of donor support for health that could reshape how policy makers will approach their support for global health.

Purine receptors are required for DHA-mediated neuroprotection against oxygen and glucose deprivation in hippocampal slices.

Docosahexaenoic acid (DHA) is important for central nervous system function during pathological states such as ischemia. DHA reduces neuronal injury in experimental brain ischemia; however, the underlying mechanisms are not well understood. In the present study, we investigated the effects of DHA on acute hippocampal slices subjected to experimental ischemia by transient oxygen and glucose deprivation (OGD) and re-oxygenation and the possible involvement of purinergic receptors as the mechanism underlying DHA-mediated neuroprotection. We observed that cellular viability reduction induced by experimental ischemia as well as cell damage and thiobarbituric acid reactive substances (TBARS) production induced by glutamate (10 mM) were prevented by hippocampal slices pretreated with DHA (5 µM). However, glutamate uptake reduction induced by OGD and re-oxygenation was not prevented by DHA. The beneficial effect of DHA against cellular viability reduction induced by OGD and re-oxygenation was blocked with PPADS (3 µM), a nonselective P2X1-5 receptor antagonist as well as with a combination of TNP-APT (100 nM) plus brilliant blue (100 nM), which blocked P2X1, P2X3, P2X2/3, and P2X7 receptors, respectively. Moreover, adenosine receptors blockade with A1 receptor antagonist DPCPX (100 nM) or with A2B receptor antagonist alloxazine (100 nM) inhibited DHA-mediated neuroprotection. The addition of an A2A receptor antagonist ZM241385 (50 nM), or A3 receptor antagonist VUF5574 (1 µM) was ineffective. Taken together, our results indicated that neuroprotective actions of DHA may depend on P2X, A1, and A2B purinergic receptors activation. Our results reinforce the notion that dietary DHA may act as a local purinergic modulator in order to prevent neurodegenerative diseases.

Genetically engineered zebrafish as models of skeletal development and regeneration.

Zebrafish (Danio rerio) are aquatic vertebrates with significant homology to their terrestrial counterparts. While zebrafish have a centuries-long track record in developmental and regenerative biology, their utility has grown exponentially with the onset of modern genetics. This is exemplified in studies focused on skeletal development and repair. Herein, the numerous contributions of zebrafish to our understanding of the basic science of cartilage, bone, tendon/ligament, and other skeletal tissues are described, with a particular focus on applications to development and regeneration. We summarize the genetic strengths that have made the zebrafish a powerful model to understand skeletal biology. We also highlight the large body of existing tools and techniques available to understand skeletal development and repair in the zebrafish and introduce emerging methods that will aid in novel discoveries in skeletal biology. Finally, we review the unique contributions of zebrafish to our understanding of regeneration and highlight diverse routes of repair in different contexts of injury. We conclude that zebrafish will continue to fill a niche of increasing breadth and depth in the study of basic cellular mechanisms of skeletal biology.

Measuring development assistance for health systems strengthening and health security: an analysis using the Creditor Reporting System database.

Background: Health systems strengthening (HSS) and health security are two pillars of universal health coverage (UHC). Investments in these areas are essential for meeting the Sustainable Development Goals and are of heightened relevance given the emergence of the 2019 novel coronavirus disease (COVID-19). This study aims to generate information on development assistance for health (DAH) for these areas, including how to track it and how funding levels align with country needs. Methods: We developed a framework to analyze the amount of DAH disbursed in 2015 for the six building blocks of the health system ('system-wide HSS') plus health security (emergency preparedness, risk management, and response) at both the global (transnational) and country level. We reviewed 2,427 of 32,801 DAH activities in the Creditor Reporting System (CRS) database (80% of the total value of disbursements in 2015) and additional public information sources. Additional aid activities were identified through a keyword search. Results: In 2015, we estimated that US$3.1 billion (13.4%) of the US$22.9 billion of DAH captured in the CRS database was for system-wide HSS and health security: US$2.5 billion (10.9%) for system-wide HSS, mostly for infrastructure, and US$0.6 billion (2.5%) for system-wide health security. US$567.1 million (2.4%) was invested in supporting these activities at the global level. If responses to individual health emergencies are included, 7.5% of total DAH (US$1.7B) was for health security. We found a correlation between DAH for HSS and maternal mortality rates, and we interpret this as evidence that HSS aid generally flowed to countries with greater need. Conclusions : Achieving UHC by 2030 will require greater investments in system-wide HSS and proactive health emergency preparedness. It may be appropriate for donors to more prominently consider country needs and global functions when investing in health security and HSS.

Alliance ruptures, impasses, and enactments: a relational perspective.

Alliance ruptures, impasses, and transference-countertransference enactments are inevitable in therapy. A growing body of evidence suggests that repairing ruptures in the alliance is related to positive outcome (Safran, Muran, & Eubanks-Carter, 2011). Our research program has led to the development of training methods to enhance therapists' abilities to detect and work constructively with alliance ruptures and negative therapeutic process (Safran et al., 2014). This article outlines relevant theoretical underpinnings, intervention principles, and empirical findings.