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

Computational structural studies of SGLT2-related polypharmacy

Introduction: Sodium Glucose Cotransporter 2 (SGLT2) is the main active transport protein involved in sodium and glucose reabsorption in the kidney. SGLT2 inhibitors (SGLT2i) are widely recommended for patients with diabetes, heart failure and chronic kidney disease (CKD). Many multimorbid patients are prescribed these compounds, raising questions about polypharmacy. We have performed a computational drug repurposing screen to identify other licensed drugs capable of binding at or near the SGLT2i active site aiming to identify compounds that could either compete with SGLT2i or inhibit sodium and glucose transport. Methods: The library of BNF listed compounds was obtained from NCBI PubChem. D-I-TASSER was used to generate monomeric structural models, and MODELLER was used to incorporate MAP-17 and empagliflozin from a reference structure (PDB 7VSI). CHARM-GUI was used to insert the protein into a membrane. The structural model was refined in a 5 nanosecond GROMACS equilibration. Docking studies using PLANTS were performed and compounds interacting with key protein residues were identified. CHARM-GUI was used to prepare membrane- and ligand-bound systems to run in GROMACS using GPUs in Google Colab. 10 nanosecond simulations were undertaken (300 Kelvin and 1 bar) to discriminate between binding and non-binding events. Results: The SGLT2-MAP17 structure was obtained in the inward-open conformation, showing good agreement with published structures. Existing SGLT2i (empagliflozin, dapagliflozin, canagliflozin, ertugliflozin) all feature in the top 1% of docked compounds in the repurposing screen. 17 compounds were investigated by MD, with all of them remaining bound to the protein in simulation. Ceftriaxone, tobramycin, clindamycin, fluvastatin, atorvastatin and ticagrelor were among the compounds with potentially significant interactions. Discussion: It is not clear whether the stable ligand interactions identified here would result in inhibition of sodium and glucose transport, or if the interactions could provide competitive inhibition for SGLT2i compounds currently used. The compounds identified are not presently recognised as interacting with SGLT2i, nor are they associated with any adverse effects suggesting inhibition of the protein. This study is limited by considering only the protein-ligand interaction and not wider pharmacokinetic or pharmacodynamic factors. Conclusion: The indication of interactions with several compounds likely to be prescribed alongside SGLT2 inhibitors, such as antibiotics, statins, and antiplatelet agents, warrants further investigation of the potential for polypharmacological complications

Changing Parental Nutrition Administration Sets Every 24 h versus Every 48 h in Newborn Infants

OBJECTIVE: To determine whether changing total parenteral nutrition fluid administration sets (TAS) every 48 h rather than every 24 h results in a greater infusate contamination rate

No new fossil fuel projects: The norm we need

A social-moral norm against new fossil fuel projects has strong potential to contribute to achieving global climate goals

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

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

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