Moral Injury, Jus Ad Bellum, and Conscientious Refusal

Although jus in bello violations create transgressive acts that cause moral injury, the primary consideration in thinking about moral injury should be jus ad bellum. If one is fighting in an ad bellum just war, then transgressive acts can be rationalized in a way that allows for consolation. But for morally sensitive combatants engaged in an ad bellum unjust war, consolation is more difficult since there is no way to justify or rationalize morally problematic deeds committed in defense of an unjust cause. Morally serious combatants should consider the question of jus ad bellum as they struggle to deal with moral injury, along with other values such as obedience and loyalty. Such an inquiry can produce further trauma when the justness of the war is called into question. The paper examines moral injury and justice in war, grounding the discussion in concrete examples: the Second World War, the Vietnam War, and the U.S. war in Iraq. It concludes that in a democracy, ordinary citizens should demonstrate solidarity with combatants suffering moral injury, since those combatants serve in wars—even unjust wars—authorized by us and fought in our names

Political Skepticism and Anarchist Themes in the American Tradition

This article describes a generally trend in American thought that is skeptical of social and political institutions. This trend can be described as a sort of philosophical anarchism. It develops out of pragmatist and skeptical criticism of absolutism in both philosophical and political systems. This paper traces this theme from its early roots in American Christian anarchism, through transcendentalists such as Emerson and Thoreau, and on to the work of William James and Jane Addams. It also outlines explicit connections between these American philosophers and anarchist authors, such as Tolstoy and Kropotkin

Science Fiction and the Boundaries of Philosophy: Exploring the Neutral Zone with Plato, Kant, and H.G. Wells

In this paper, I consider the difficulty of distinguishing between science fiction and philosophy. The boundary between these genres is somewhat vague. There is a “neutral zone” separating the genres. But this neutral zone is often transgressed. One key distinction considered here is that between entertainment and edification. Another crucial element is found in the importance of the author’s apparent self-consciousness of these distinctions. Philosophy seeks to edify, and philosophers are often deliberately focused on thinking about the question of the borders that distinguish genres. Science fiction is more interested in entertainment, and narrative authors tend to care less about policing the border. This distinction is a pragmatic one. And canonical authors often violate the boundary. I examine key authors to make this point, including Plato, Kant, and H.G. Wells. My discussion shows that these canonical authors wandered into the neutral zone in their own work, reminding us that the boundaries we draw around genres are arbitrary and subject to transgression

Site selective C–H functionalization of Mitragyna alkaloids reveals a molecular switch for tuning opioid receptor signaling efficacy

Mitragynine (MG) is an indole alkaloid from kratom plant that binds opioid receptors and as such presents a scaffold for the development of atypical opioid receptor modulators. Here, the authors report a synthetic method for selective functionalization of the C11 position of MG, and show that this position is essential for fine-tuning opioid receptor signaling efficacy

Maternal γδ T cells shape offspring pulmonary type 2 immunity in a microbiota-dependent manner.

Immune development is profoundly influenced by vertically transferred cues. However, little is known about how maternal innate-like lymphocytes regulate offspring immunity. Here, we show that mice born from γδ T cell-deficient (TCRδ-/-) dams display an increase in first-breath-induced inflammation, with a pulmonary milieu selectively enriched in type 2 cytokines and type 2-polarized immune cells, when compared with the progeny of γδ T cell-sufficient dams. Upon helminth infection, mice born from TCRδ-/- dams sustain an increased type 2 inflammatory response. This is independent of the genotype of the pups. Instead, the offspring of TCRδ-/- dams harbors a distinct intestinal microbiota, acquired during birth and fostering, and decreased levels of intestinal short-chain fatty acids (SCFAs), such as pentanoate and hexanoate. Importantly, exogenous SCFA supplementation inhibits type 2 innate lymphoid cell function and suppresses first-breath- and infection-induced inflammation. Taken together, our findings unravel a maternal γδ T cell-microbiota-SCFA axis regulating neonatal lung immunity

Single-cell discovery and multiomic characterization of therapeutic targets in multiple myeloma

UNLABELLED: Multiple myeloma (MM) is a highly refractory hematologic cancer. Targeted immunotherapy has shown promise in MM but remains hindered by the challenge of identifying specific yet broadly representative tumor markers. We analyzed 53 bone marrow (BM) aspirates from 41 MM patients using an unbiased, high-throughput pipeline for therapeutic target discovery via single-cell transcriptomic profiling, yielding 38 MM marker genes encoding cell-surface proteins and 15 encoding intracellular proteins. Of these, 20 candidate genes were highlighted that are not yet under clinical study, 11 of which were previously uncharacterized as therapeutic targets. The findings were cross-validated using bulk RNA sequencing, flow cytometry, and proteomic mass spectrometry of MM cell lines and patient BM, demonstrating high overall concordance across data types. Independent discovery using bulk RNA sequencing reiterated top candidates, further affirming the ability of single-cell transcriptomics to accurately capture marker expression despite limitations in sample size or sequencing depth. Target dynamics and heterogeneity were further examined using both transcriptomic and immuno-imaging methods. In summary, this study presents a robust and broadly applicable strategy for identifying tumor markers to better inform the development of targeted cancer therapy. SIGNIFICANCE: Single-cell transcriptomic profiling and multiomic cross-validation to uncover therapeutic targets identifies 38 myeloma marker genes, including 11 transcribing surface proteins with previously uncharacterized potential for targeted antitumor therapy

Safety and tolerability of long-term treatment with darolutamide in patients with metastatic castration-resistant prostate cancer

Background In patients with metastatic castration-resistant prostate cancer, darolutamide was well tolerated for 25 months, but minimal long-term safety data are available. Methods Treatment-emergent adverse events (TEAEs) for patients receiving darolutamide for a median of 38 months (n = 13) are described in this pooled analysis of individual patient data from phase 1/2 studies. Results All patients reported TEAEs (mostly grade 1/2). The most common TEAEs were diarrhea, abdominal pain, and nausea. Serious TEAEs were reported in six patients (none related to darolutamide). All treatment-related TEAEs (n = 5) were grade 1. Conclusions Long-term darolutamide treatment was well tolerated; no new safety signals observed

Evolutionary genomics of a cold-adapted diatom: Fragilariopsis cylindrus

The Southern Ocean houses a diverse and productive community of organisms1, 2. Unicellular eukaryotic diatoms are the main primary producers in this environment, where photosynthesis is limited by low concentrations of dissolved iron and large seasonal fluctuations in light, temperature and the extent of sea ice3, 4, 5, 6, 7. How diatoms have adapted to this extreme environment is largely unknown. Here we present insights into the genome evolution of a cold-adapted diatom from the Southern Ocean, Fragilariopsis cylindrus8, 9, based on a comparison with temperate diatoms. We find that approximately 24.7 per cent of the diploid F. cylindrus genome consists of genetic loci with alleles that are highly divergent (15.1 megabases of the total genome size of 61.1 megabases). These divergent alleles were differentially expressed across environmental conditions, including darkness, low iron, freezing, elevated temperature and increased CO2. Alleles with the largest ratio of non-synonymous to synonymous nucleotide substitutions also show the most pronounced condition-dependent expression, suggesting a correlation between diversifying selection and allelic differentiation. Divergent alleles may be involved in adaptation to environmental fluctuations in the Southern Ocean