To identify Janus kinase (JAK) inhibitors that selectively target gastrointestinal tissues with limited systemic exposures, a class of imidazopyrrolopyridines with a range of physical properties was prepared and evaluated. We identified compounds with low intrinsic permeability and determined a correlation between permeability and physicochemical properties, clogP and tPSA, for a subset of compounds. This low intrinsic permeability translated into compounds displaying high colonic exposure and low systemic exposure after oral dosing at 25 mg/kg in mouse. In a mouse PK/PD model, oral dosing of lead compound 2 demonstrated dose-dependent inhibition of pSTAT phosphorylation in colonic explants post-oral dose but low systemic exposure and no measurable systemic pharmacodynamic activity. We thus demonstrate the utility of JAK inhibitors with low intrinsic permeability as a feasible approach to develop gut-restricted, pharmacologically active molecules with a potential advantage over systemically available compounds that are limited by systemic on-target adverse events.

Hydrogen sulfide (H2S) is a cytoprotective redox-active metabolite that signals through protein persulfidation (R-SSnH). Despite the known importance of persulfidation, tissue-specific persulfidome profiles and their associated functions are not well characterized, specifically under conditions and interventions known to modulate H2S production. We hypothesize that dietary restriction (DR), which increases lifespan and can boost H2S production, expands tissue-specific persulfidomes. Here, we find protein persulfidation enriched in liver, kidney, muscle, and brain but decreased in heart of young and aged male mice under two forms of DR, with DR promoting persulfidation in numerous metabolic and aging-related pathways. Mice lacking cystathionine γ-lyase (CGL) have overall decreased tissue protein persulfidation numbers and fail to functionally augment persulfidomes in response to DR, predominantly in kidney, muscle, and brain. Here, we define tissue- and CGL-dependent persulfidomes and how diet transforms their makeup, underscoring the breadth for DR and H2S to impact biological processes and organismal health.

Most people have been both the victim and the perpetrator of a moral transgression at some point in their lives; this article asks whether one set of moral experiences is easier to remember than the other, and why.In Study 1, we documented this basic asymmetry, finding that individuals recalled more instances in which they were the victim of a moral transgression than instances in which they were the perpetrator.In Study 2, we found that this asymmetry in memory arises because experiences of being the victim are perceived more negatively than experiences of being the perpetrator. In Studies 3 and 4, we demonstrated the critical role of intent in this asymmetry, finding that victim memories emphasize perpetrator intent to a greater degree than do perpetrator memories (Study 3), and that the memory asymmetry disappeared when individuals recalled unintentional moral violations (Study 4). Finally, in Study 5, we ruled out a potential alternative mechanism for these effects-that of self-protective motivation on the part of perpetrators. We found that the threat associated with the moral violation moderated victim (but not perpetrator) memories, a finding that is inconsistent with a motivational account for perpetrator memories. This research demonstrates that perceived agency shapes emotional experience and autobiographical memory and speaks to the importance of studying morality as it occurs in everyday contexts.

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