John Calvin, 2 Samuel 2:8-32 and Resistance to Civil Government: Supreme Equivocation or Mastery of Contextual Exegesis?

Abstract Over the years, it has been the considered view of some scholars that John Calvin regarded popular armed resistance to duly appointed but abusive civil rulers as illegitimate in the world of the 16th century and, by analogy, in the world of today. Instead, they are of the view that the legitimacy of forceful resistance to a tyrannical civil magistrate as subsequently developed by the later Huguenots, Scottish Covenanters and English Parliamentarians was rooted in the thought of Theodore Beza as it allegedly diverged from that of Calvin. They apparently base this view exclusively on a reading of the Institutes 4.20.24-30. This paper examines whether Calvin’s sermons on 2 Samuel, preached in 1562, puts to rest accusations of equivocation raised by the infamous “perhaps” of paragraph 31; and if so, whether they evidence a development in Calvin’s thought which stands in irreconcilable contradiction to the position expressed in the last chapter of the Institutes. Opsomming Johannes Calvyn, 2 Samuel 2:8-32 en weerstand teen die burgerlike owerheid: uiterste dubbelsinnigheid of beheersing van kontekstuele eksegese? Deur die jare was dit die oorwoë mening van kenners dat Johannes Calvyn gewapende weerstand teen die regmatige – hoewel onderdrukkende – owerheid as onwettig in die wêreld van die 16de eeu beskou het, en dat dit daarom ook onwettig vir vandag is. Daarenteen is hulle van mening dat die regmatigheid van gewelddadige weerstand teen die onderdrukkende owerheid, soos dit later deur die Hugenote, Skotse ‘Covenanters’ en Engelse Parlementariërs ontwikkel is, eerder in die denke van Theodore Beza gegrond was, na bewering in afwyking van Calvyn. Oënskynlik word hierdie mening uitsluitend gebaseer op ’n lesing van die Institusie 4.20.24-30. Hierdie artikel ondersoek of Calvyn se preke oor 2 Samuel, gehou in 1562, die aantyging van dubbelsinnigheid wat deur die berugte “miskien” van paragraaf 31 opgeroep word, kan weerlê. En indien wel, of hierdie preke ’n ontwikkeling in Calvyn se denke aantoon, wat in ’n onversoenbare teenstrydigheid staan met die posisie wat in die laaste hoofstuk van die Institusie ingeneem word.    https://doi.org/10.19108/KOERS.82.2.235

Lighting the Path: What IPCC energy pathways tell us about Paris-aligned policies and investments

This report outlines key implications for governments and investors aiming to align their policies and investments with the 1.5°C target of the Paris Agreement, based on different energy pathways published by the Intergovernmental Panel on Climate Change (IPCC) in its Sixth Assessment Report, published in April 2022.This report shows that significant structural changes are required in the energy sector to align with pathways limiting warming to 1.5°C. The pathways consistent with the IPCC's assessment of feasible and sustainable deployment of Carbon Dioxide Removal and Carbon Capture and Storage technologies leave no room for delayed action. The oil and gas phase-out timelines presented in this report constitute the ambition level consistent with the best estimates of the current and future capacity of mitigation technologies. Accordingly, this report presents the key implications for governments and financial institutions aiming to align their policies and investments with feasible 1.5°C pathways. Its recommendations are designed to guide the understanding of the Paris alignment, consistent with the IPCC findings, and should inform plans to strengthen and amplify policy interventions

Existing fossil fuel extraction would warm the world beyond 1.5 °C

The Paris climate goals and the Glasgow Climate Pact require anthropogenic carbon dioxide (CO2) emissions to decline to net zero by mid-century. This will require overcoming carbon lock-in throughout the energy system. Previous studies have focused on ‘committed emissions’ from capital investments in energy-consuming infrastructure, or potential (committed and uncommitted) emissions from fossil fuel reserves. Here we make the first bottom-up assessment of committed CO2 emissions from fossil fuel-producing infrastructure, defined as existing and under-construction oil and gas fields and coal mines. We use a commercial model of the world’s 25 000 oil and gas fields and build a new dataset on coal mines in the nine largest coal-producing countries. Our central estimate of committed emissions is 936 Gt CO2, comprising 47% from coal, 35% from oil and 18% from gas. We find that staying within a 1.5 °C carbon budget (50% probability) implies leaving almost 40% of ‘developed reserves’ of fossil fuels unextracted. The finding that developed reserves substantially exceed the 1.5 °C carbon budget is robust to a Monte Carlo analysis of reserves data limitations, carbon budget uncertainties and oil prices. This study contributes to growing scholarship on the relevance of fossil fuel supply to climate mitigation. Going beyond recent warnings by the International Energy Agency, our results suggest that staying below 1.5 °C may require governments and companies not only to cease licensing and development of new fields and mines, but also to prematurely decommission a significant portion of those already developed.Peer Reviewe

Bisphosphonate inhibitors of squalene synthase protect cells against cholesterol‐dependent cytolysins

Certain species of pathogenic bacteria damage tissues by secreting cholesterol‐dependent cytolysins, which form pores in the plasma membranes of animal cells. However, reducing cholesterol protects cells against these cytolysins. As the first committed step of cholesterol biosynthesis is catalyzed by squalene synthase, we explored whether inhibiting this enzyme protected cells against cholesterol‐dependent cytolysins. We first synthesized 22 different nitrogen‐containing bisphosphonate molecules that were designed to inhibit squalene synthase. Squalene synthase inhibition was quantified using a cell‐free enzyme assay, and validated by computer modeling of bisphosphonate molecules binding to squalene synthase. The bisphosphonates were then screened for their ability to protect HeLa cells against the damage caused by the cholesterol‐dependent cytolysin, pyolysin. The most effective bisphosphonate reduced pyolysin‐induced leakage of lactate dehydrogenase into cell supernatants by >80%, and reduced pyolysin‐induced cytolysis from >75% to <25%. In addition, this bisphosphonate reduced pyolysin‐induced leakage of potassium from cells, limited changes in the cytoskeleton, prevented mitogen‐activated protein kinases cell stress responses, and reduced cellular cholesterol. The bisphosphonate also protected cells against another cholesterol‐dependent cytolysin, streptolysin O, and protected lung epithelial cells and primary dermal fibroblasts against cytolysis. Our findings imply that treatment with bisphosphonates that inhibit squalene synthase might help protect tissues against pathogenic bacteria that secrete cholesterol‐dependent cytolysins

Bile acid biosynthesis in Smith-Lemli-Opitz syndrome bypassing cholesterol: Potential importance of pathway intermediates

Bile acids are the end products of cholesterol metabolism secreted into bile. They are essential for the absorption of lipids and lipid soluble compounds from the intestine. Here we have identified a series of unusual Δ5-unsaturated bile acids in plasma and urine of patients with Smith-Lemli-Opitz syndrome (SLOS), a defect in cholesterol biosynthesis resulting in elevated levels of 7-dehydrocholesterol (7-DHC), an immediate precursor of cholesterol. Using liquid chromatography – mass spectrometry (LC-MS) we have uncovered a pathway of bile acid biosynthesis in SLOS avoiding cholesterol starting with 7-DHC and proceeding through 7-oxo and 7β-hydroxy intermediates. This pathway also occurs to a minor extent in healthy humans, but elevated levels of pathway intermediates could be responsible for some of the features SLOS. The pathway is also active in SLOS affected pregnancies as revealed by analysis of amniotic fluid. Importantly, intermediates in the pathway, 25-hydroxy-7-oxocholesterol, (25R)26-hydroxy-7-oxocholesterol, 3β-hydroxy-7-oxocholest-5-en-(25R)26-oic acid and the analogous 7β-hydroxysterols are modulators of the activity of Smoothened (Smo), an oncoprotein that mediates Hedgehog (Hh) signalling across membranes during embryogenesis and in the regeneration of postembryonic tissue. Computational docking of the 7-oxo and 7β-hydroxy compounds to the extracellular cysteine rich domain of Smo reveals that they bind in the same groove as both 20S-hydroxycholesterol and cholesterol, known activators of the Hh pathway

In Vitro and In Silico Analyses of the Inhibition of Human Aldehyde Oxidase by Bazedoxifene, Lasofoxifene, and Structural Analogues

Aldehyde oxidase (AOX1) is a molybdo-flavoprotein and has emerged as a drug-metabolizing enzyme of potential therapeutic importance because drugs have been identified as AOX1 substrates. Selective oestrogen receptor modulators (SERM), which are drugs used to treat and prevent various conditions, differentially inhibit AOX1 catalytic activity. Tamoxifen, raloxifene, and nafoxidine are selective oestrogen receptor modulators (SERMs) reported to inhibit the catalytic activity of human aldehyde oxidase 1 (AOX1). How these drugs interact with AOX1 and whether other SERMs inhibit this drug-metabolizing enzyme are not known. Therefore, a detailed in vitro and in silico study involving parent drugs and their analogues was conducted to investigate the effect of specific SERMs, particularly acolbifene, bazedoxifene, and lasofoxifene on AOX1 catalytic activity, as assessed by carbazeran 4-oxidation, an AOX1-selective catalytic marker. The rank-order in the potency (based on IC50 values) of AOX1 inhibition by SERMs was raloxifene > bazedoxifene ~ lasofoxifene > tamoxifen > acolbifene. Inhibition of liver cytosolic AOX1 by bazedoxifene, lasofoxifene, and tamoxifen was competitive, whereas that by raloxifene was noncompetitive. Loss of 1-azepanylethyl group increased the inhibitory potency of bazedoxifene, whereas the N-oxide group decreased it. The 7-hydroxy group and the substituted pyrrolidine ring attached to the tetrahydronaphthalene structure contributed to AOX1 inhibition by lasofoxifene. These results are supported by molecular docking simulations in terms of predicted binding modes, encompassing binding orientation and efficiency, and analysis of key interactions, particularly hydrogen bonds. The extent of AOX1 inhibition by bazedoxifene was increased by estrone sulfate and estrone. In summary, SERMs differentially inhibited human AOX1 catalytic activity. Structural features of bazedoxifene and lasofoxifene contributed to AOX1 inhibition, whereas those of acolbifene rendered it considerably less susceptible to AOX1 inhibition. Overall, our novel biochemical findings and molecular docking analyses provide new insights into the interaction between SERMs and AOX1. Structural features of bazedoxifene and lasofoxifene contribute to AOX1 inhibition, whereas those of acolbifene render it considerably less susceptible to AOX1 inhibition. Our novel biochemical findings, together with molecular docking analyses, provide new insights into the differential inhibitory effect of SERMs on the catalytic activity of human AOX1, how SERMs bind to AOX1, and increase our understanding of the AOX1 pharmacophore in the inhibition of AOX1 by drugs and other chemicals

Exploring the role of phase-out policies for low-carbon energy transitions: the case of the German Energiewende

The energy sector plays a significant role in reaching the ambitious climate policy target of limiting the global temperature increase to well below 2°C. To this end, technological change has to be redirected and accelerated in the direction of zero-carbon solutions. Given the urgency and magnitude of the climate change challenge it has been argued that this calls for a policy mix which simultaneously supports low-carbon solutions and also deliberately drives the discontinuation of the established technological regime. Yet, the effect of such phase-out policies on the development and diffusion of low-carbon technologies has received little attention in empirical research so far. This paper addresses this gap by taking the case of the transition of the German electricity generation system towards renewable energies – the so-called Ener-giewende. Based on a survey of innovation activities of German manufacturers of renewable power gener-ation technologies conducted in 2014 it explores the impact such destabilization policies – most prominent-ly Germany’s nuclear phase-out policy – may have on technological change in renewable energies. By drawing on descriptive statistics and combining insights from earlier regression analyses we find evidence that Germany’s nuclear phase-out policy had a positive influence on manufacturers’ innovation expendi-tures for renewable energies and was seen as the by far most influential policy instrument for the further expansion of renewable energies in Germany. The insights resulting from our explorative analysis have important implications for the literature on policy mixes and sustainability transitions regarding the ‘flip sides’ to innovation and the crucial importance of destabilization policies for unleashing ‘destructive crea-tion’. We close by discussing policy repercussions for ongoing debates on policies for accelerating the phase-out of coal to meet climate change targets

Ten new insights in climate science 2023

Non-technical summary. We identify a set of essential recent advances in climate change research with high policy relevance, across natural and social sciences: (1) looming inevitability and implications of overshooting the 1.5°C warming limit, (2) urgent need for a rapid and managed fossil fuel phase-out, (3) challenges for scaling carbon dioxide removal, (4) uncertainties regarding the future contribution of natural carbon sinks, (5) intertwinedness of the crises of biodiversity loss and climate change, (6) compound events, (7) mountain glacier loss, (8) human immobility in the face of climate risks, (9) adaptation justice, and (10) just transitions in food systems. Technical summary. The Intergovernmental Panel on Climate Change Assessment Reports provides the scientific foundation for international climate negotiations and constitutes an unmatched resource for researchers. However, the assessment cycles take multiple years. As a contribution to cross- and interdisciplinary understanding of climate change across diverse research communities, we have streamlined an annual process to identify and synthesize significant research advances. We collected input from experts on various fields using an online questionnaire and prioritized a set of 10 key research insights with high policy relevance. This year, we focus on: (1) the looming overshoot of the 1.5°C warming limit, (2) the urgency of fossil fuel phase-out, (3) challenges to scale-up carbon dioxide removal, (4) uncertainties regarding future natural carbon sinks, (5) the need for joint governance of biodiversity loss and climate change, (6) advances in understanding compound events, (7) accelerated mountain glacier loss, (8) human immobility amidst climate risks, (9) adaptation justice, and (10) just transitions in food systems. We present a succinct account of these insights, reflect on their policy implications, and offer an integrated set of policy-relevant messages. This science synthesis and science communication effort is also the basis for a policy report contributing to elevate climate science every year in time for the United Nations Climate Change Conference. Social media summary. We highlight recent and policy-relevant advances in climate change research – with input from more than 200 experts