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Summary: Stem cell therapies for degenerative cartilage disease are limited by an incomplete understanding of hyaline cartilage formation and maintenance. Human bone marrow stromal cells/skeletal stem cells (hBMSCs/SSCs) produce stable hyaline cartilage when attached to hyaluronic acid-coated fibrin microbeads (HyA-FMBs), yet the mechanism remains unclear. In vitro, hBMSC/SSC/HyA-FMB organoids exhibited reduced BMP signaling early in chondrogenic differentiation, followed by restoration of BMP signaling in chondrogenic IGFBP5+/MGP+ cells. Subsequently, human-induced pluripotent stem cell (hiPSC)-derived sclerotome cells were established (BMP inhibition) and then treated with transforming growth factor β (TGF-β) −/+ BMP2 and growth differentiation factor 5 (GDF5) (BMP signaling activation). TGF-β alone elicited a weak chondrogenic response, but TGF-β/BMP2/GDF5 led to delamination of SOX9+ aggregates (chondrospheroids) with high expression of COL2A1, ACAN, and PRG4 and minimal expression of COL10A1 and ALP in vitro. While transplanted hBMSCs/SSCs/HyA-FMBs did not heal articular cartilage defects in immunocompromised rodents, chondrospheroid-derived cells/HyA-FMBs formed non-hypertrophic cartilage that persisted until at least 5 months in vivo.

The goal of Community Service activities with the theme Writing and Publication of Classroom Action Research (CAR) is to increase educators' competence in the field of CAR, inspire innovation and improve learning, disseminate CAR knowledge and practice in the classroom, and encourage collaboration and knowledge sharing. The activity's goal was to reach 35 junior high school teachers in Kupang Regency, NTT Province. Carried out through the use of andragogy learning methodologies, including needs assessment, content preparation, and interactive training. The end findings demonstrate that the training participants' understanding of CAR has greatly expanded, their desire and self-innovation have developed, and they have continued with a commitment to use the outcomes of the CAR training, as well as subsequent training activities will be carried out in order to improve instructors' capacities to enhance their understanding and skills in CAR-related issues.

In the last decade the world has experienced a number of global crises which triggered economic downturns. Impacts from the global financial crisis, the global COVID pandemic, and Russia’s invasion of Ukraine trigger instability in financial markets. This paper explores similarities and differences between these crises based on inflation and its energy-related components. A Vector Autoregressive (VAR) model is used to analyze both EU-level trends, as well as data for Romania. The findings indicate idiosyncratic shifts in the relationships between variables. The changes are often specific to individual shocks and the policy context. How policy makers respond to these shocks will also impact the fiscal space, the borrowing costs of countries, and the cost of servicing debt, which risks a return to the type of austerity policies that slowed down the post-financial crisis recovery. There is a need for more detailed research and investigations in policy responses designed to respond to ongoing events.

Abstract Background The prevalence of sedentary behaviour has concurrently risen with multiple cardiometabolic risk markers independent of physical activity levels. Office-based workers accumulate the highest levels of sitting time during occupational times. This study aims to investigate the short-term effects of using height-adjustable sit-to-stand workstations on cardiometabolic risk markers of office-based workers in South Africa. Results Sixty-two office-based workers were randomized into intervention (n = 44), and the control group (n = 18). Small improvements were observed in BMI, blood pressure, and cholesterol levels in this cohort. Conclusion This preliminary investigation confirms that short-term height-adjustable sit-stand interventions are effective in reducing workplace sitting time and selected health outcomes. South Africa has been attributed with the highest burden of obesity in Sub-Saharan Africa, as a result, there is a need to implement long-term workplace intervention to reverse these implications. Trial registration Pan African Clinical Trial Registry, PACTR201911656014962 on the 12th of November 2019.

Using Montenegro as a case study, this paper evaluates the viability of currency substitution, in this case euroization, as a response to increased financial volatility. Proponents of euroization outline a series of expected benefits, while critics point to what they perceive as much larger costs. The paper contrasts the macroeconomic developments of Montenegro and how it fared during the Global Financial Crisis and the shock triggered by the Covid-19 pandemic with the performance of its regional peers and the euro area overall. The findings are contrasted to how the various expectations played out for Montenegro, drawing further lessons on the role of monetary policy and domestic monetary sovereignty.

This paper compares the actual and potential resources derived from the G20’s Debt Service Suspension Initiative and the actual and potential resources from International Monetary Fund’s 2021 allocation of Special Drawing Rights. These programs were two main sources of support for 73 vulnerable countries during height of the COVID-19 pandemic. For these countries, Special Drawing Rights provided much greater potential support when compared to the Debt Service Suspension Initiative. Special Drawing Rights deployed more actual resources as well. When these programs are evaluated from the perspective of the countries receiving assistance, Special Drawing Rights are found to have several characteristics that are more desirable. As such, as a tool, Special Drawing Rights have several advantages that should be taken into account during discussions about policy responses to global challenges in the future.

Human pluripotent stem cells (hPSCs) can provide a platform to model bone organogenesis and disease. To reflect the developmental process of the human skeleton, hPSC differentiation methods should include osteogenic progenitors (OPs) arising from three distinct embryonic lineages: the paraxial mesoderm, lateral plate mesoderm, and neural crest. Although OP differentiation protocols have been developed, the lineage from which they are derived, as well as characterization of their genetic and molecular differences, has not been well reported. Therefore, to generate lineage-specific OPs from human embryonic stem cells and human induced pluripotent stem cells, we employed stepwise differentiation of paraxial mesoderm-like cells, lateral plate mesoderm-like cells, and neural crest-like cells toward their respective OP subpopulation. Successful differentiation, confirmed through gene expression and in vivo assays, permitted the identification of transcriptomic signatures of all three cell populations. We also report, for the first time, high FGF1 levels in neural crest-derived OPs-a notable finding given the critical role of fibroblast growth factors (FGFs) in osteogenesis and mineral homeostasis. Our results indicate that FGF1 influences RUNX2 levels, with concomitant changes in ERK1/2 signaling. Overall, our study further validates hPSCs power to model bone development and disease and reveals new, potentially important pathways influencing these processes.

SARS-CoV-2 (CoV2) infected, asymptomatic individuals are an important contributor to COVID transmission. CoV2-specific immunoglobulin (Ig)-as generated by the immune system following infection or vaccination-has helped limit CoV2 transmission from asymptomatic individuals to susceptible populations (e.g. elderly). Here, we describe the relationships between COVID incidence and CoV2 lineage, viral load, saliva Ig levels (CoV2-specific IgM, IgA and IgG), and ACE2 binding inhibition capacity in asymptomatic individuals between January 2021 and May 2022. These data were generated as part of a large university COVID monitoring program in Ohio, United States of America, and demonstrate that COVID incidence among asymptomatic individuals occurred in waves which mirrored those in surrounding regions, with saliva CoV2 viral loads becoming progressively higher in our community until vaccine mandates were established. Among the unvaccinated, infection with each CoV2 lineage (pre-Omicron) resulted in saliva Spike-specific IgM, IgA, and IgG responses, the latter increasing significantly post-infection and being more pronounced than N-specific IgG responses. Vaccination resulted in significantly higher Spike-specific IgG levels compared to unvaccinated infected individuals, and uninfected vaccinees' saliva was more capable of inhibiting Spike function. Vaccinees with breakthrough Delta infections had Spike-specific IgG levels comparable to those of uninfected vaccinees; however, their ability to inhibit Spike binding was diminished. These data are consistent with COVID vaccines having achieved hoped-for effects in our community, including the generation of mucosal antibodies that inhibit Spike and lower community viral loads, and suggest breakthrough Delta infections were not due to an absence of vaccine-elicited Ig, but instead limited Spike binding activity in the face of high community viral loads.

In light of two recent global economic shocks, the global financial crisis of 2007/08 and the COVID-19 pandemic, this paper analyzes the relationships between global shocks and the national stock markets, looking to trends in volatility for the leading stock indices in six CEE countries, namely Austria, Bulgaria, Czech Republic, Hungary, Poland, and Romania, and indices from Germany (DAX) and the United States (S&P 500). The selected indices include the largest domestic companies in each country and make up most of the domestic market capitalization. For the analysis we used Garman-Klass (GK) volatility estimator, as the volatility was considered the most important proxy for market uncertainty. Then we used a simple correlation matrix to show initial tendencies. Also, the Johansen's test was used to determine if the indices are cointegrated and if this relationship has changed significantly in the non-crisis periods. We analyze Granger causality and the network approach as proposed by Diebold and Yilmaz (2015). The GK volatility results were individualized in three periods: 2007-2011 as a proxy for the global financial crisis and European sovereign debt; 2012-2019 representing a period of economic recovery and ultimately 2020-2021 representing the data points for the COVID-19 global pandemic. We find that particularly during periods of global distress, correlations between patterns of volatility for the stock market indices from these countries increase, and they exhibit stronger patterns of cointegration. These findings highlight the increasing connectivity in global financial markets and added challenges in crafting portfolio diversification strategies based on geography of stock holdings.

The initial shock from and response to the Global Financial Crisis (GFC) in 2008 had a profound impact on the fiscal balances and subsequently the government debt ratios of countries in the European Union (EU). This paper examines the relationship fiscal consolidation measures and the changes in debt ratios that followed. The findings highlight that the negative feedback of fiscal consolidation on economic growth in this context can translate into increases, rather than decreases in government debt ratios. As debt levels in most European Union countries are reaching record levels in the aftermath of Covid-19, these results warn of the risks of a stunted recovery if a similar approach as in the aftermath of the GFC is pursued.

Introduction: Erythropoietin (EPO), produced in the kidney in a hypoxia responsive manner, is required for red blood cell production. In non-erythroid tissue, EPO increases endothelial cell production of nitric oxide (NO) and endothelial nitric oxide synthase (eNOS) that regulates vascular tone to improve oxygen delivery. This contributes to EPO cardioprotective activity in mouse models. Nitric oxide treatment in mice shifts hematopoiesis toward the erythroid lineage, increases red blood cell production and total hemoglobin. In erythroid cells, nitric oxide can also be generated by hydroxyurea metabolism that may contribute to hydroxyurea induction of fetal hemoglobin. We find that during erythroid differentiation, EPO induces neuronal nitric oxide synthase (nNOS) and that neuronal nitric oxide synthase is required for normal erythropoietic response.Methods: Wild type (WT) mice and mice with targeted deletion of nNOS (nNOS−/−) and eNOS (eNOS−/−) were assessed for EPO stimulated erythropoietic response. Bone marrow erythropoietic activity was assessed in culture by EPO dependent erythroid colony assay and in vivo by bone marrow transplantation into recipient WT mice. Contribution of nNOS to EPO stimulated cell proliferation was assessed in EPO dependent erythroid cells and in primary human erythroid progenitor cell cultures.Results: EPO treatment increased hematocrit similarly in WT and eNOS−/− mice and showed a lower increase in hematocrit nNOS−/− mice. Erythroid colony assays from bone marrow cells were comparable in number from wild type, eNOS−/− and nNOS−/− mice at low EPO concentration. Colony number increased at high EPO concentration is seen only in cultures from bone marrow cells of wild type and eNOS−/− mice but not from nNOS−/− mice. Colony size with high EPO treatment also exhibited a marked increase in erythroid cultures from wild type and eNOS−/− mice but not from nNOS−/− mice. Bone marrow transplant from nNOS−/− mice into immunodeficient mice showed engraftment at comparable levels to WT bone marrow transplant. With EPO treatment, the increase in hematocrit was blunted in recipient mice that received with nNOS−/− donor marrow compared with recipient mice that received WT donor marrow. In erythroid cell cultures, addition of nNOS inhibitor resulted in decreased EPO dependent proliferation mediated in part by decreased EPO receptor expression, and decreased proliferation of hemin induced differentiating erythroid cells.Discussion: EPO treatment in mice and in corresponding cultures of bone marrow erythropoiesis suggest an intrinsic defect in erythropoietic response of nNOS−/− mice to high EPO stimulation. Transplantation of bone marrow from donor WT or nNOS−/− mice into recipient WT mice showed that EPO treatment post-transplant recapitulated the response of donor mice. Culture studies suggest nNOS regulation of EPO dependent erythroid cell proliferation, expression of EPO receptor and cell cycle associated genes, and AKT activation. These data provide evidence that nitric oxide modulates EPO dose dependent erythropoietic response.

Cut-and-paste |$K$| -theory has recently emerged as an important variant of higher algebraic |$K$| -theory. However, many of the powerful tools used to study classical higher algebraic |$K$| -theory do not yet have analogues in the cut-and-paste setting. In particular, there does not yet exist a sensible notion of the Dennis trace for cut-and-paste |$K$| -theory. In this paper we address the particular case of the |$K$| -theory of polyhedra, also called scissors congruence |$K$| -theory. We introduce an explicit, computable trace map from the higher scissors congruence groups to group homology, and use this trace to prove the existence of some nonzero classes in the higher scissors congruence groups. We also show that the |$K$| -theory of polyhedra is a homotopy orbit spectrum. This fits into Thomason's general framework of |$K$| -theory commuting with homotopy colimits, but we give a self-contained proof. We then use this result to re-interpret the trace map as a partial inverse to the map that commutes homotopy orbits with algebraic |$K$| -theory. [ABSTRACT FROM AUTHOR]