👤 Carni Lipson

Moral inclusiveness-the scope of one's moral circle-has traditionally been studied as a single, global trait. This study instead applied latent profile analysis (LPA) to uncover nuanced moral inclusiveness profiles spanning nested layers of relational proximity (family, community, global citizen, and nonhuman living beings). The study looked across four validated scales-Kindness, Compassion, Global-Mindedness, and Speciesism-and further examined how these profiles relate to trauma, mental health, and spirituality. A cross-sectional sample of 763 U.S. participants completed measures assessing moral inclusiveness, mental health, lifetime and recent traumatic events, and three spiritual dimensions: general spirituality, spiritual decline, and awakened awareness. LPA revealed five distinct profiles: Ingroup Concern, Outgroup Concern, Average Overall Concern, Universal Empathy, and Lovers. The Ingroup Concern class exhibited the highest levels of psychopathology, the most recent traumatic events, and elevated spiritual decline. The Universal Empathy and Lovers classes reported low current distress, minimal spiritual decline, and significantly higher awakened awareness, suggesting they experienced adversity yet still maintained meaning and/or guidance. Lifetime trauma exposure alone did not preclude a broad moral scope of inclusion: the Ingroup Concern and Universal Empathy classes both reported substantial trauma histories but diverged in moral inclusiveness, possibly due to differences in spiritual injury and ongoing stress. These findings reveal that a more parochial or limited moral scope is associated with lifetime and recent adversity, current mental health challenges, and spiritual injury. More expansive concern for human and fellow living beings is associated with positive spiritual engagement and fewer immediate negative life events. Show less

Tumor regression following immune checkpoint blockade (ICB) is often associated with immune-related adverse events (irAEs), marked by inflammation in non-cancerous tissues. This study was undertaken to investigate the functional relationship between anti-tumor and anti-self immunity, to facilitate irAE management while promoting anti-tumor immunity. Multiple biopsies from tumor and inflamed tissues were collected from a patient with melanoma experiencing both tumor regression and irAEs on ICB, who underwent rapid autopsy. Immune cells infiltrating melanoma lesions and inflamed normal tissues were subjected to gene expression profiling with multiplex qRT-PCR for 122 candidate genes. Subsequently, immunohistochemistry was conducted to assess the expression of 14 candidate markers of immune cell subsets and checkpoints. TCR-beta sequencing was used to explore T cell clonal repertoires across specimens. While genes involved in MHC I/II antigen presentation, IFN signaling, innate immunity and immunosuppression were abundantly expressed across specimens, irAE tissues over-expressed certain genes associated with immunosuppression (CSF1R, IL10RA, IL27/EBI3, FOXP3, KLRG1, SOCS1, TGFB1), including those in the COX-2/PGE2 pathway (IL1B, PTGER1/EP1 and PTGER4/EP4). Immunohistochemistry revealed similar proportions of immunosuppressive cell subsets and checkpoint molecules across samples. TCRseq did not indicate common TCR repertoires across tumor and inflammation sites, arguing against shared antigen recognition between anti-tumor and anti-self immunity in this patient. This comprehensive study of a single patient with melanoma experiencing both tumor regression and irAEs on ICB explores the immune landscape across these tissues, revealing similarities between anti-tumor and anti-self immunity. Further, it highlights expression of the COX-2/PGE2 pathway, which is known to be immunosuppressive and potentially mediates ICB resistance. Ongoing clinical trials of COX-2/PGE2 pathway inhibitors targeting the major COX-2 inducer IL-1B, COX-2 itself, or the PGE2 receptors EP2 and EP4 present new opportunities to promote anti-tumor activity, but may also have the potential to enhance the severity of ICB-induced irAEs. Show less

Protein complexes often represent an ensemble of different assemblies with distinct functions and regulation. This increased complexity is enabled by the variety of protein diversification mechanisms that exist at every step of the protein biosynthesis pathway, such as alternative splicing and post transcriptional and translational modifications. The resulting variation in subunits can generate compositionally distinct protein assemblies. These different forms of a single protein complex may comprise functional variances that enable response and adaptation to varying cellular conditions. Despite the biological importance of this layer of complexity, relatively little is known about the compositional heterogeneity of protein complexes, mostly due to technical barriers of studying such closely related species. Here, we show that native mass spectrometry (MS) offers a way to unravel this inherent heterogeneity of protein assemblies. Our approach relies on the advanced Orbitrap mass spectrometer capable of multistage MS analysis across all levels of protein organization. Specifically, we have implemented a two-step fragmentation process in the inject flatapole device, which was converted to a linear ion trap, and can now probe the intact protein complex assembly, through its constituent subunits, to the primary sequence of each protein. We demonstrate our approach on the yeast homotetrameric FBP1 complex, the rate-limiting enzyme in gluconeogenesis. We show that the complex responds differently to changes in growth conditions by tuning phosphorylation dynamics. Our methodology deciphers, on a single instrument and in a single measurement, the stoichiometry, kinetics, and exact position of modifications, contributing to the exposure of the multilevel diversity of protein complexes. Show less