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Peter Lombard’s First Book of the Sentences presents formidable questions concerning the principle of the Son’s generation. Addressing a gap in contemporary scholarship, this article examines Lombard’s foundational exposition of the Father’s power and will to generate. Placing Lombard in dialogue with Thomas Aquinas, this study traces the development of this doctrine across Aquinas’s career, from his commentary on the Sentences to De potentia and the Summa theologiae. Our analysis adopts Aquinas’s own framework to investigate a series of questions: whether generation is an act of nature or will; whether the power to generate is part of omnipotence; whether it is essential or relational; and whether the Son possesses this power. This study finds that Aquinas’s conclusions often converge with Lombard’s intuitions. Both affirm that generation is by nature while simultaneously accompanied by a concomitant will, and that the generative power is rooted in the divine essence. Aquinas’s analysis, however, represents a significant metaphysical development. A key evolution is traced in Aquinas’s understanding of the power to generate, which shifts from being a quasi-natural power distinct from omnipotence to a form of paternal omnipotence. His characterization of this power also matures from being a middle ground between the essential and the relational to being principally essential, signifying the relation of paternity only obliquely. This trajectory toward a firmer grounding in the divine essence is supported by an increasingly refined set of arguments for the Son’s unicity, with principles like the determination of nature and divine simplicity becoming more prominent in his later works. By charting these developments, this article demonstrates how Aquinas builds upon Lombard’s foundational intuitions to construct a more systematic and robust Trinitarian theology. Ultimately, our analysis illuminates the intellectual journey from sound doctrinal intuition to profound metaphysical articulation, where the tenets of faith are secured by a cogent intellectual framework. Our analysis also offers a counter-narrative to contemporary assumptions, challenging modern conceptions of power as a zero-sum game and of freedom as mere arbitrary choice.

This article argues that Thomas Aquinas’s exegesis of the parables in his commentary on the Gospel of Matthew contains—if only in skeletal form, with certain aspects more fully developed than others—the outline of a comprehensive treatise on Christian eschatology. Aquinas approaches parables with a nuanced perspective, acknowledging their inherent obscurity while also emphasizing their capacity to guide minds toward the truth. He understands their dual purpose as both concealing divine mysteries from the ill-intentioned and revealing them to the receptive. Distinguishing his approach from Albert the Great’s, Aquinas’s commentary features substantial eschatological components. Drawing on primary sources, this article examines these elements, starting with the unknowability of the end of time, which serves to promote vigilance. This article then treats death and particular judgment, the damned’s twofold punishment (the poena damni and the poena sensus), and the righteous’s varied, eternal reward, concluding with the Parousia, inseparably linked to the general resurrection, the final judgment, and the renewal of the world. Finally, this article shows how Aquinas’s engagement with these parables provides a robust, biblically-rooted exploration of the Last Things.

The ability to screen compounds in a high-throughput manner is essential in the process of small molecule drug discovery. Critical to the success of screening strategies is the proper design of the assay, often implying a compromise between ease/speed and a biologically relevant setting. Leishmaniasis is a major neglected disease with limited therapeutic options. In order to streamline efforts for the design of productive drug screens against Leishmania, we compared the efficiency of two screening methods, one targeting the free living and easily cultured promastigote (insect-infective) stage, the other targeting the clinically relevant but more difficult to culture intra-macrophage amastigote (mammal-infective) stage. Screening of a 909-member library of bioactive compounds against Leishmania donovani revealed 59 hits in the promastigote primary screen and 27 in the intracellular amastigote screen, with 26 hits shared by both screens. This suggested that screening against the promastigote stage, although more suitable for automation, fails to identify all active compounds and leads to numerous false positive hits. Of particular interest was the identification of one compound specific to the infective amastigote stage of the parasite. This compound affects intracellular but not axenic parasites, suggesting a host cell-dependent mechanism of action, opening new avenues for anti-leishmanial chemotherapy.

Oxidative stress is a central part of innate immune-induced neurodegeneration. However, the transcriptomic landscape of central nervous system (CNS) innate immune cells contributing to oxidative stress is unknown, and therapies to target their neurotoxic functions are not widely available. Here, we provide the oxidative stress innate immune cell atlas in neuroinflammatory disease and report the discovery of new druggable pathways. Transcriptional profiling of oxidative stress–producing CNS innate immune cells identified a core oxidative stress gene signature coupled to coagulation and glutathione-pathway genes shared between a microglia cluster and infiltrating macrophages. Tox-seq followed by a microglia high-throughput screen and oxidative stress gene network analysis identified the glutathione-regulating compound acivicin, with potent therapeutic effects that decrease oxidative stress and axonal damage in chronic and relapsing multiple sclerosis models. Thus, oxidative stress transcriptomics identified neurotoxic CNS innate immune populations and may enable discovery of selective neuroprotective strategies. Oxidative stress can promote neurodegeneration. Akassoglou and colleagues describe Tox-seq, a functional single-cell RNA sequencing method to identify oxidative stress transcriptional signatures in CNS-resident cells. Tox-seq identified coagulation and glutathione-redox pathway genes that are coupled to oxidative stress and that could be targeted by the glutathione-regulating small molecule acivicin.

The membrane-bound transcription factor ATF6α plays a cytoprotective role in the unfolded protein response (UPR), required for cells to survive ER stress. Activation of ATF6α promotes cell survival in cancer models. We used cell-based screens to discover and develop Ceapins, a class of pyrazole amides, that block ATF6α signaling in response to ER stress. Ceapins sensitize cells to ER stress without impacting viability of unstressed cells. Ceapins are highly specific inhibitors of ATF6α signaling, not affecting signaling through the other branches of the UPR, or proteolytic processing of its close homolog ATF6β or SREBP (a cholesterol-regulated transcription factor), both activated by the same proteases. Ceapins are first-in-class inhibitors that can be used to explore both the mechanism of activation of ATF6α and its role in pathological settings. The discovery of Ceapins now enables pharmacological modulation all three UPR branches either singly or in combination. Newly made proteins must be folded into specific three-dimensional shapes before they can perform their roles in cells. Many proteins are folded in a cell compartment called the endoplasmic reticulum. The cell closely monitors the quality of the work done by this compartment. If the endoplasmic reticulum has more proteins to fold than it can handle, unfolded or misfolded proteins accumulate and trigger a stress response called the unfolded protein response. This increases the capacity of the endoplasmic reticulum to fold proteins to match the demand. However, if the stress persists, then the unfolded protein response instructs the cell to die to protect the rest of the body. A protein called ATF6α is one of three branches of the unfolded protein response. This protein is found in the endoplasmic reticulum where it is inactive. Endoplasmic stress causes ATF6α to move from the endoplasmic reticulum to another compartment called the Golgi apparatus. There, two enzymes cut ATF6α to release a fragment of the protein that then moves to the nucleus to increase the production of the machinery needed to fold proteins in the endoplasmic reticulum. Errors in protein folding can cause serious diseases in humans and other animals. Drugs that target ATF6α might be able to regulate part of the unfolded protein response to treat these diseases. However, no drugs that act on ATF6α had been identified. Now, two groups of researchers have independently identified small molecules that specifically target ATF6α. Gallagher et al. screened over 100,000 compounds for their ability to reduce the activity of ATF6α-regulated genes. The experiments reveal that a class of small molecules termed Ceapins can selectively block the activity of ATF6α during endoplasmic reticulum stress, but had no effect on other proteins involved in the unfolded protein response. Furthermore, when human cells experiencing stress were treated with Ceapins, a greater number of cells died in comparison to cells that had not received Ceapins. An accompanying study by Gallagher and Walter reports on the mechanism by which Ceapins act on ATF6α. Independently, Plate et al. identified a type of small molecule that can activate ATF6. Together, the findings of Gallagher et al. and Plate et al. may lead to the development of new drugs for treating diseases associated with incorrect protein folding in the endoplasmic reticulum.

Activation of innate immunity and deposition of blood-derived fibrin in the central nervous system (CNS) occur in autoimmune and neurodegenerative diseases, including multiple sclerosis (MS) and Alzheimer’s disease (AD). However, the mechanisms that link disruption of the blood–brain barrier (BBB) to neurodegeneration are poorly understood, and exploration of fibrin as a therapeutic target has been limited by its beneficial clotting functions. Here we report the generation of monoclonal antibody 5B8, targeted against the cryptic fibrin epitope γ 377–395 , to selectively inhibit fibrin-induced inflammation and oxidative stress without interfering with clotting. 5B8 suppressed fibrin-induced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase activation and the expression of proinflammatory genes. In animal models of MS and AD, 5B8 entered the CNS and bound to parenchymal fibrin, and its therapeutic administration reduced the activation of innate immunity and neurodegeneration. Thus, fibrin-targeting immunotherapy inhibited autoimmunity- and amyloid-driven neurotoxicity and might have clinical benefit without globally suppressing innate immunity or interfering with coagulation in diverse neurological diseases. Fibrin deposition occurs after the blood–brain barrier is breached. Akassoglou and colleagues generate a therapeutic monoclonal antibody that targets a cryptic fibrin epitope to suppress activation of innate immune responses in the CNS and diminish neuroinflammation.

Chagas Disease, a WHO- and NIH-designated neglected tropical disease, is endemic in Latin America and an emerging infection in North America and Europe as a result of population moves. Although a major cause of morbidity and mortality due to heart failure, as well as inflicting a heavy economic burden in affected regions, Chagas Disease elicits scant notice from the pharmaceutical industry because of adverse economic incentives. The discovery and development of new routes to chemotherapy for Chagas Disease is a clear priority. The similarity between the membrane sterol requirements of pathogenic fungi and those of the parasitic protozoon Trypanosoma cruzi, the causative agent of Chagas human cardiopathy, has led to repurposing anti-fungal azole inhibitors of sterol 14α-demethylase (CYP51) for the treatment of Chagas Disease. To diversify the therapeutic pipeline of anti-Chagasic drug candidates we exploited an approach that included directly probing the T. cruzi CYP51 active site with a library of synthetic small molecules. Target-based high-throughput screening reduced the library of ∼104,000 small molecules to 185 hits with estimated nanomolar K(D) values, while cross-validation against T. cruzi-infected skeletal myoblast cells yielded 57 active hits with EC(50) <10 µM. Two pools of hits partially overlapped. The top hit inhibited T. cruzi with EC(50) of 17 nM and was trypanocidal at 40 nM. The hits are structurally diverse, demonstrating that CYP51 is a rather permissive enzyme target for small molecules. Cheminformatic analysis of the hits suggests that CYP51 pharmacology is similar to that of other cytochromes P450 therapeutic targets, including thromboxane synthase (CYP5), fatty acid ω-hydroxylases (CYP4), 17α-hydroxylase/17,20-lyase (CYP17) and aromatase (CYP19). Surprisingly, strong similarity is suggested to glutaminyl-peptide cyclotransferase, which is unrelated to CYP51 by sequence or structure. Lead compounds developed by pharmaceutical companies against these targets could also be explored for efficacy against T. cruzi.

Phosphorylation of the α-subunit of initiation factor 2 (eIF2) controls protein synthesis by a conserved mechanism. In metazoa, distinct stress conditions activate different eIF2α kinases (PERK, PKR, GCN2, and HRI) that converge on phosphorylating a unique serine in eIF2α. This collection of signaling pathways is termed the ‘integrated stress response’ (ISR). eIF2α phosphorylation diminishes protein synthesis, while allowing preferential translation of some mRNAs. Starting with a cell-based screen for inhibitors of PERK signaling, we identified a small molecule, named ISRIB, that potently (IC50 = 5 nM) reverses the effects of eIF2α phosphorylation. ISRIB reduces the viability of cells subjected to PERK-activation by chronic endoplasmic reticulum stress. eIF2α phosphorylation is implicated in memory consolidation. Remarkably, ISRIB-treated mice display significant enhancement in spatial and fear-associated learning. Thus, memory consolidation is inherently limited by the ISR, and ISRIB releases this brake. As such, ISRIB promises to contribute to our understanding and treatment of cognitive disorders. The synthesis of proteins is an essential step in many biological processes, including memory, and drugs that inhibit protein synthesis are known to impair memory in rodents. It is thought that the brain needs these proteins to convert short-term memories into long-term memories through a process known as consolidation. A protein called EIF2α has a key role in the regulation of protein synthesis, and has also been implicated in memory. EIF2α can be activated as a result of being phosphorylated by any of four protein kinases: these are in turn activated by processes that subject cells to stress, such as viral infection, UV light or—in the case of a kinase known as PERK—the accumulation of unfolded proteins in a cellular organelle called the endoplasmic reticulum. Activation of EIF2α downregulates most protein synthesis inside the cell, but upregulates the production of a small number of key regulatory molecules: these changes help cells to cope with whatever stressful event they have just experienced. To obtain further insight into the cellular stress response, Sidrauski et al. screened a large library of compounds in search of one that inhibits PERK. They identified a molecule—known as ISRIB—which acts downstream of all four protein kinases by reversing the effects of EIF2α phosphorylation. ISRIB is the first molecule shown to have this effect, and thus represents an important tool for investigating the stress response inside cells. When Sidrauski et al. injected ISRIB into mice, the animals showed improved memory: for example, they learnt to locate a hidden platform in a water maze more rapidly than controls. This suggests that ISRIB could be used to explore the mechanisms that underlie memory consolidation, and possibly even as a memory enhancer. Moreover, given that many tumor cells exploit the cellular stress response to aid their own growth, ISRIB may have potential as a novel chemotherapeutic agent.

Dipeptidyl aminopeptidases (DPAPs) are cysteine proteases that cleave dipeptides from the N-terminus of protein substrates and have been shown to play important roles in many pathologies including parasitic diseases such as malaria, toxoplasmosis and Chagas's disease. Inhibitors of the mammalian homologue cathepsin C have been used in clinical trials as potential drugs to treat chronic inflammatory disorders, thus proving that these enzymes are druggable. In Plasmodium species, DPAPs play important functions at different stages of parasite development, thus making them potential antimalarial targets. Most DPAP inhibitors developed to date are peptide-based or peptidomimetic competitive inhibitors. Here, we used a high throughput screening approach to identify novel inhibitor scaffolds that block the activity of Plasmodium falciparum DPAP1. Most of the hits identified in this screen also inhibit Plasmodium falciparum DPAP3, cathepsin C, and to a lesser extent other malarial clan CA proteases, indicating that these might be general DPAP inhibitors. Interestingly, our mechanism of inhibition studies indicate that most hits are allosteric inhibitors, which opens a completely new strategy to inhibit these enzymes, study their biological function, and potentially develop new inhibitors as starting points for drug development.

The targeting of parasite cysteine proteases with small molecules is emerging as a possible approach to treat tropical parasitic diseases such as sleeping sickness, Chagas' disease, and malaria. The homology of parasite cysteine proteases to the human cathepsins suggests that inhibitors originally developed for the latter may be a source of promising lead compounds for the former. We describe here the screening of a unique ∼ 2,100-member cathepsin inhibitor library against five parasite cysteine proteases thought to be relevant in tropical parasitic diseases. Compounds active against parasite enzymes were subsequently screened against cultured Plasmodium falciparum, Trypanosoma brucei brucei and/or Trypanosoma cruzi parasites and evaluated for cytotoxicity to mammalian cells. The end products of this effort include the identification of sub-micromolar cell-active leads as well as the elucidation of structure-activity trends that can guide further optimization efforts.