Activation of APE1/Ref-1 is dependent on reactive oxygen species generated after purinergic receptor stimulation by ATP

Apurinic apyrimidinic endonuclease redox effector factor-1 (APE1/Ref-1) is involved both in the base excision repair (BER) of DNA lesions and in the eukaryotic transcriptional regulation. APE1/Ref-1 is regulated at both the transcriptional and post-translational levels, through control of subcellular localization and post-translational modification. In response to stress conditions, several cell types release ATP, which exerts stimulatory effects on eukaryotic cells via the purinergic receptors (P2) family. By using western blot and immunofluorescence analysis on a human tumour thyroid cell line (ARO), we demonstrate that purinergic stimulation by extracellular ATP induces quick cytoplasm to nucleus translocation of the protein at early times and its neosynthesis at later times. Continuous purinergic triggering by extracellular ATP released by ARO cells is responsible for the control of APE1/Ref-1 intracellular level. Interference with intracellular pathways activated by P2 triggering demonstrates that Ca(2+) mobilization and intracellular reactive oxygen species (ROS) production are responsible for APE1/Ref-1 translocation. The APE1/Ref-1 activities on activator protein-1 (AP-1) DNA binding and DNA repair perfectly match its nuclear enrichment upon ATP stimulation. The biological relevance of our data is reinforced by the observation that APE1/Ref-1 stimulation by ATP protects ARO cells by H(2)O(2)-induced cell death. Our data provide new insights into the complex mechanisms regulating APE1/Ref-1 functions

Identification of secondary targets of N-containing bisphosphonates in mammalian cells via parallel competition analysis of the barcoded yeast deletion collection

Growth competition assays using barcoded yeast deletion-mutants reveal the molecular targets of nitrogen containing bisphosphonates used for the treatment of bone cancers and osteoporosis

The 2023 Latin America report of the Lancet Countdown on health and climate change: the imperative for health-centred climate-resilient development

In 2023, a series of climatological and political events unfolded, partly driving forward the global climate and health agenda while simultaneously exposing important disparities and vulnerabilities to climate-related events. On the policy front, a significant step forward was marked by the inaugural Health Day at COP28, acknowledging the profound impacts of climate change on health. However, the first-ever Global Stocktake showed an important gap between the current progress and the targets outlined in the Paris Agreement, underscoring the urgent need for further and decisive action. From a Latin American perspective, some questions arise: How do we achieve the change that is needed? How to address the vulnerabilities to climate change in a region with longstanding social inequities? How do we promote intersectoral collaboration to face a complex problem such as climate change? The debate is still ongoing, and in many instances, it is just starting. The renamed regional centre Lancet Countdown Latin America (previously named Lancet Countdown South America) expanded its geographical scope adding Mexico and five Central American countries: Costa Rica, El Salvador, Guatemala, Honduras, and Panama, as a response to the need for stronger collaboration in a region with significant social disparities, including research capacities and funding. The centre is an independent and multidisciplinary collaboration that tracks the links between health and climate change in Latin America, following the global Lancet Countdown’s methodologies and five domains. The Lancet Countdown Latin America work hinges on the commitment of 23 regional academic institutions, United Nations agencies, and 34 researchers who generously contribute their time and expertise. Building from the first report, the 2023 report of the Lancet Countdown Latin America, presents 34 indicators that track the relationship between health and climate change up to 2022, aiming at providing evidence to public decisionmaking with the purpose of improving the health and wellbeing of Latin American populations and reducing social inequities through climate actions focusing on health. This report shows that Latin American populations continue to observe a growing exposure to changing climatic conditions. A warming trend has been observed across all countries in Latin America, with severe direct impacts. In 2022, people were exposed to ambient temperatures, on average, 0.38 ◦C higher than in 1986–2005, with Paraguay experiencing the highest anomaly (+1.9 ◦C), followed by Argentina (+1.2 ◦C) and Uruguay (+0.9 ◦C) (indicator 1.1.1). In 2013–2022, infants were exposed to 248% more heatwave days and people over 65 years old were exposed to 271% more heatwave days than in 1986–2005 (indicator 1.1.2). Also, compared to 1991–2000, in 2013–2022, there were 256 and 189 additional annual hours per person, during which ambient heat posed at least moderate and high risk of heat stress during light outdoor physical activity in Latin America, respectively (indicator 1.1.3). Finally, the region had a 140% increase in heat-related mortality from 2000–2009 to 2013–2022 (indicator 1.1.4). Changes in ecosystems have led to an increased risk of wildfires, exposing individuals to very or extremely high fire danger for more extended periods (indicator 1.2.1). Additionally, the transmission potential for dengue by Aedes aegypti mosquitoes has risen by 54% from 1951–1960 to 2013–2022 (indicator 1.3), which aligns with the recent outbreaks and increasing dengue cases observed across Latin America in recent months. Based on the 2023 report of the Lancet Countdown Latin America, there are three key messages that Latin America needs to further explore and advance for a health-centred climate-resilient development. Latin American countries require intersectoral public policies that simultaneously increase climate resilience, reduce social inequities, improve population health, and reduce greenhouse gas (GHG) emissions. The findings show that adaptation policies in Latin America remain weak, with a pressing need for robust vulnerability and adaptation (V&A) assessments to address climate risks effectively. Unfortunately, such assessments are scarce. Up to 2021, Brazil is the only country that has completed and officially reported a V&A to the 2021 Global Survey conducted by the World Health Organization (WHO). Argentina, Guatemala, and Panama have also conducted them, but they have not been reported (indicator 2.1.1). Similarly, efforts in developing and implementing Health National Adaptation Plans (HNAPs) are varied and limited in scope. Brazil, Chile, and Uruguay are the only countries that have an HNAP (indicator 2.1.2). Moreover, self-reported city-level climate change risk assessments are very limited in the region (indicator 2.1.3). The collaboration between meteorological and health sectors remains insufficient, with only Argentina, Brazil, Colombia, and Guatemala self-reporting some level of integration (indicator 2.2.1), hindering comprehensive responses to climate-related health risks in the region. Additionally, despite the urgent need for action, there has been minimal progress in increasing urban greenspaces across the region since 2015, with only Colombia, Nicaragua, and Venezuela showing slight improvements (indicator 2.2.2). Compounding these challenges is the decrease in funding for climate change adaptation projects in Latin America, as evidenced by the 16% drop in funds allocated by the Green Climate Fund (GCF) in 2022 compared to 2021. Alarmingly, none of the funds approved in 2022 were directed toward climate change and health projects, highlighting a critical gap in addressing health-related climate risks (indicator 2.2.3). From a vulnerability perspective, the Mosquito Risk Index (MoRI) indicates an overall decrease in severe mosquitoborne disease risk in the region due to improvements in water, sanitation, and hygiene (WASH) (indicator 2.3.1). Brazil and Paraguay were the only countries that showed an increase in this indicator. It is worth noting that significant temporal variation within and between countries still persists, suggesting inadequate preparedness for climate-related changes. Overall, population health is not solely determined by the health sector, nor are climate policies a sole responsibility of the environmental sector. More and stronger intersectoral collaboration is needed to pave development pathways that consider solid adaptation to climate change, greater reductions of GHG emissions, and that increase social equity and population health. These policies involve sectors such as finance, transport, energy, housing, health, and agriculture, requiring institutional structures and policy instruments that allow long-term intersectoral collaboration. Latin American countries need to accelerate an energy transition that prioritises people’s health and wellbeing, reduces energy poverty and air pollution, and maximises health and economic gains. In Latin America, there is a notable disparity in energy transition, with electricity generation from coal increasing by an average of 2.6% from 1991–2000 to 2011–2020, posing a challenge to efforts aimed at phasing out coal (indicator 3.1.1). However, this percentage increase is conservative as it may not include all the fossil fuels for thermoelectric electricity generation, especially during climate-related events and when hydropower is affected (Panel 4). Yet, renewable energy sources have been growing, increasing by an average of 5.7% during the same period. Access to clean fuels for cooking remains a concern, with 46.3% of the rural population in Central America and 23.3% in South America lacking access to clean fuels in 2022 (indicator 3.1.2). It is crucial to highlight the concerning overreliance on fossil fuels, particularly liquefied petroleum gas (LPG), as a primary cooking fuel. A significant majority of Latin American populations, approximately 74.6%, rely on LPG for cooking. Transitioning to cleaner heating and cooking alternatives could also have a health benefit by reducing household air pollution-related mortality. Fossil fuels continue to dominate road transport energy in Latin America, accounting for 96%, although some South American countries are increasing the use of biofuels (indicator 3.1.3). Premature mortality attributable to fossil-fuel-derived PM2.5 has shown varied trends across countries, increasing by 3.9% from 2005 to 2020 across Latin America, which corresponds to 123.5 premature deaths per million people (indicator 3.2.1). The Latin American countries with the highest premature mortality rate attributable to PM2.5 in 2020 were Chile, Peru, Brazil, Colombia, Mexico, and Paraguay. Of the total premature deaths attributable to PM2.5 in 2020, 19.1% was from transport, 12.3% from households, 11.6% from industry, and 11% from agriculture. From emission and capture of GHG perspective, commodity-driven deforestation and expansion of agricultural land remain major contributors to tree cover loss in the region, accounting for around 80% of the total loss (indicator 3.3). Additionally, animal-based food production in Latin America contributes 85% to agricultural CO2 equivalent emissions, with Argentina, Brazil, Panama, Paraguay, and Uruguay ranking highest in per capita emissions (indicator 3.4.1). From a health perspective, in 2020, approximately 870,000 deaths were associated with imbalanced diets, of which 155,000 (18%) were linked to high intake of red and processed meat and dairy products (indicator 3.4.2). Energy transition in Latin America is still in its infancy, and as a result, millions of people are currently exposed to dangerous levels of air pollution and energy poverty (i.e., lack of access to essential energy sources or services). As shown in this report, the levels of air pollution, outdoors and indoors, are a significant problem in the whole region, with marked disparities between urban and rural areas. In 2022, Peru, Chile, Mexico, Guatemala, Colombia, El Salvador, Brazil, Uruguay, Honduras, Panama, and Nicaragua were in the top 100 most polluted countries globally. Transitioning to cleaner sources of energy, phasing out fossil fuels, and promoting better energy efficiency in the industrial and housing sectors are not only climate mitigation measures but also huge health and economic opportunities for more prosperous and healthy societies. Latin American countries need to increase climate finance through permanent fiscal commitments and multilateral development banks to pave climate-resilient development pathways. Climate change poses significant economic costs, with investments in mitigation and adaptation measures progressing slowly. In 2022, economic losses due to weather-related extreme events in Latin America were US$15.6 billion –an amount mainly driven by floods and landslides in Brazil–representing 0.28 America’s Gross Domestic Product (GDP) (indicator 4.1.1). In contrast to high-income countries, most of these losses lack insurance coverage, imposing a substantial financial strain on affected families and governments. Heat-related mortality among individuals aged 65 and older in Latin America reached alarming levels, with losses exceeding the equivalent of the average income of 451,000 people annually (indicator 4.1.2). Moreover, the total potential income loss due to heat-related labour capacity reduction amounted to 1.34 disproportionately affecting the agriculture and construction sectors (indicator 4.1.3). Additionally, the economic toll of premature mortality from air pollution was substantial, equivalent to a significant portion of regional GDP (0.61 On a positive note, clean energy investments in the region increased in 2022, surpassing fossil fuel investments. However, in 2020, all countries reviewed continued to offer net-negative carbon prices, revealing fossil fuel subsidies totalling US$23 billion. Venezuela had the highest net subsidies relative to current health expenditure (123%), followed by Argentina (10.5%), Bolivia (10.3%), Ecuador (8.3%), and Chile (5.6%) (indicator 4.2.1). Fossil fuel-based energy is today more expensive than renewable energy. Fossil fuel burning drives climate change and damages the environment on which people depend, and air pollution derived from the burning of fossil fuels causes seven million premature deaths each year worldwide, along with a substantial burden of disease. Transitioning to sustainable, zero-emission energy sources, fostering healthier food systems, and expediting adaptation efforts promise not only environmental benefits but also significant economic gains. However, to implement mitigation and adaptation policies that also improve social wellbeing and prosperity, stronger and solid financial systems are needed. Climate finance in Latin American countries is scarce and strongly depends on political cycles, which threatens adequate responses to the current and future challenges. Progress on the climate agenda is lagging behind the urgent pace required. While engagement with the intersection of health and climate change is increasing, government involvement remains inadequate. Newspaper coverage of health and climate change has been on the rise, peaking in 2022, yet the proportion of climate change articles discussing health has declined over time (indicator 5.1). Although there has been significant growth in the number of scientific papers focusing on Latin America, it still represents less than 4% of global publications on the subject (indicator 5.3). And, while health was mentioned by most Latin American countries at the UN General Debate in 2022, only a few addressed the intersection of health and climate change, indicating a lack of awareness at the governmental level (indicator 5.4). The 2023 Lancet Countdown Latin America report underscores the cascading and compounding health impacts of anthropogenic climate change, marked by increased exposure to heatwaves, wildfires, and vector-borne diseases. Specifically, for Latin America, the report emphasises three critical messages: the urgent action to implement intersectoral public policies that enhance climate resilience across the region; the pressing need to prioritise an energy transition that focuses on health co-benefits and wellbeing, and lastly, that need for increasing climate finance by committing to sustained fiscal efforts and engaging with multilateral development banks. By understanding the problems, addressing the gaps, and taking decisive action, Latin America can navigate the challenges of climate change, fostering a more sustainable and resilient future for its population. Spanish and Portuguese translated versions of this Summary can be found in Appendix B and C, respectively. The full translated report in Spanish is available in Appendix D

The 2022 South America report of The Lancet Countdown on health and climate change: trust the science. Now that we know, we must act

The health of South American populations is being severely impacted by increasing climate change-driven environmental changes. Exacerbated by increased social inequities and vulnerability, deforestation, land degradation, and global climate variabilities in sea temperature, can potentially lead to extreme weather and climate events, magnifying the negative effects of climate change on health. Understanding the direct and indirect exposure routes to climate hazards and the effects on health and wellbeing is critical to design successful and effective evidence-based adaptation and mitigation plans and policies. This report is part of the Lancet Countdown's broader efforts to develop expertise and understanding of the links between health and climate change at the regional level. The Lancet Countdown South America (LCSA), a newly launched chapter of the Lancet Countdown, is an independent, multidisciplinary academic collaboration dedicated to tracking the links between public health and climate change in South America (SA). This collaboration brings together 21 academic institutions and UN agencies with 28 researchers representing various disciplines. The data and results provided in this report for the 12 countries of the region,∗ explore in regional detail the results of the 2022 global Lancet Countdown report and provide the evidence to support targeted response strategies for decision-makers. Its findings and conclusions represent the consensus of experts across multiple fields, covering 25 indicators summarised below in four key messages

Caratterizzazione biochimica delle fasi organica e minerale del tessuto osseo nel ratto

Dottorato di ricerca in biochimica. 7. ciclo. Tutore L. Moro. Coordinatore B. De BernardConsiglio Nazionale delle Ricerche - Biblioteca Centrale - P.le Aldo Moro, 7, Rome; Biblioteca Nazionale Centrale - P.za Cavalleggeri, 1, Florence / CNR - Consiglio Nazionale delle RichercheSIGLEITItal

The Influence of Orchidectomy on Collagen Glycosylation of Trabecular Bone in Rat

Peer Reviewe

17β-Estradiol and Tamoxifen Prevent the Over-Glycosylation of Rat Trabecular Bone Collagen Induced by Ovariectomy

Peer Reviewe

Extracellular ATP stimulates the early growth response protein 1 (Egr-1) via a protein kinase C-dependent pathway in the human osteoblastic HOBIT cell line.

Extracellular nucleotides exert an important role in controlling cell physiology by activating intracellular signalling cascades. Osteoblast HOBIT cells express P2Y(1) and P2Y(2) G-protein-coupled receptors, and respond to extracellular ATP by increasing cytosolic calcium concentrations. Early growth response protein 1 (Egr-1) is a C(2)H(2)-zinc-finger-containing transcriptional regulator responsible for the activation of several genes involved in the control of cell proliferation and apoptosis, and is thought to have a central role in osteoblast biology. We show that ATP treatment of HOBIT cells increases Egr-1 protein levels and binding activity via a mechanism involving a Ca(2+)-independent protein kinase C isoform. Moreover, hypotonic stress and increased medium turbulence, by inducing ATP release, result in a similar effect on Egr-1. Increased levels of Egr-1 protein expression and activity are achieved at very early times after stimulation (5 min), possibly accounting for a rapid way for changing the osteoblast gene-expression profile. A target gene for Egr-1 that is fundamental in osteoblast physiology, COL1A2, is up-regulated by ATP stimulation of HOBIT cells in a timescale that is compatible with that of Egr-1 activation