Abstract Ionotropic glutamate receptors AMPAR and NMDAR are central to synaptic transmission and key targets in neurological disease therapy. Here, we developed a de novo design pipeline combining a generative neural network, AlphaFold2 structural predictions, and molecular dynamics to create short, high-affinity, receptor-selective peptide modulators. The algorithm targets receptor hotspots, optimizing for minimal contact distance and high structural confidence, and avoids mode collapse through position-specific scoring matrix integration. In silico evaluation of top candidates exhibited strong binding affinity, low RMSD fluctuations, and stable hydrogen bonding. Selectivity tests confirmed minimal cross-binding between AMPAR- and NMDAR-specific peptides. Top candidates were synthesized and evaluated in in vitro experiments. In rat cortical and hippocampal cultures, peptides induced robust, concentration-dependent intracellular Ca2+ influx, abolished by extracellular calcium removal or selective antagonists (CNQX, MK-801), thus confirming the positive modulatory action of designed peptides. Cross-inhibition assays demonstrated strict receptor specificity. Although calcium responses were lower than those elicited by conventional ligands (AMPA and NMDA), functional modulation was confirmed. This integrated computational–experimental framework enables efficient development of receptor-specific peptide modulators and offers a promising strategy for therapeutic discovery.
Abstract Chronic inflammatory skin diseases are characterized by epithelial barrier dysfunction and immune dysregulation, yet the epithelial-intrinsic mechanisms that initiate inflammation remain poorly understood. TMEM79 is a dermatitis-associated transmembrane protein expressed in keratinocytes, but how its loss promotes skin disease remains unclear. Here, using keratinocyte-specific Tmem79 conditional knockout (cKO) mice and TMEM79-deficient human keratinocytes, we find that TMEM79 is required for proper epithelial differentiation and barrier formation, and that its loss induces keratinocyte stress and ferroptosis-associated lipid peroxidation. Longitudinal analysis of neonatal and early postnatal Tmem79-deficient skin revealed disrupted epidermal homeostasis and early type I IFN signaling preceding the later emergence of type 17 inflammation. Mechanistically, genetic ablation of Sting1, but not Mavs, ameliorated dermatitis and downstream type 17 inflammation, while IL-17A was required for subsequent epidermal hyperplasia. These findings establish STING-dependent signaling as an upstream driver of skin immune activation and pathology. Together, our findings link early-life epithelial stress to innate immune activation and suggest that targeting lipid peroxidation or STING signaling may help prevent inflammatory skin disease progression.
Abstract Public opinion of hate crimes may be malleable because these acts are understood through victims' varying social identities. We investigate whether violent attacks provoke different reactions when framed around victims' national rather than religious identities. We first document media coverage of hate crimes, showing that more than 20% of headlines about anti-Jewish hate crimes use nationalist frames, invoking Israel. We then analyze discourse surrounding a high-profile anti-Jewish attack and demonstrate the prominence of nationalist framing. In two survey experiments with U.S. adults, we show widespread aversion to religiously motivated violence, but greater ambivalence toward attacks motivated by nationalism. Specifically, opposition to physically violent attacks against Jews weakens when framed through the victim's support for Israel rather than their religious identification. Similarly, opposition to attacks on Muslims and Hindus declines when linked to Palestinian and Indian nationalism, respectively. While Americans display near-universal opposition to religious bigotry, nationalist frames erode public condemnation of identity-based violence.
Abstract Cortical cytoarchitecture and lamination are believed to remain stable after completion of development. Here we demonstrate that early postnatal and adult (P45-P60) inactivation of the Reln gene results in dispersion of layer II-III neocortical neurons which invade layer I. In addition, neuronal mispositioning was observed in the dentate gyrus, the CA1-CA3 regions and in the cerebellum. Interestingly, inactivation of the Reln gene at adult stages resulted in altered oscillatory network activity in different cortical regions and in the nucleus accumbens. Moreover, Reelin deficiency increased depression-like behaviour and impaired long-term memory consolidation. Thus, besides its crucial developmental role, Reelin is important in maintaining adult cortical lamination and rhythmic neuronal synchronization. These results suggest that, in addition to physiological and synaptic plasticity, there may be a certain degree of laminar structural plasticity in adult stages, which may lead to reconsidering the origin of layering alterations observed in neuropsychiatric diseases.
Abstract Societies often misperceive their own normative center. Individuals may believe that distinctive, conservative, or ideologically committed positions are more widely shared than they actually are, sustaining pluralistic ignorance even when private attitudes are moderate. Yet little is known about how perceived norms become systematically organized under conditions of uncertainty. We propose that norm perceptions are structured around socially salient reference points, including identity-defining or ideologically committed subgroups, and only partially calibrated by individuals’ private attitudes. Across two preregistered studies, we test this representational account of norm perception in distinct social ecologies. Study 1 examines norm inference among 550 adults from Israel's ultra-Orthodox community, a context characterized by strong social norms and hierarchies. Study 2 extends the analysis cross-nationally using survey data from 21,233 respondents in 57 countries on perceived gender norms. Using theory-constrained regression models, we fixed the intercept to alternative candidate reference points and estimated adjustment from these anchors as a function of respondents’ private attitudes. Across studies, perceived norms were better represented relative to contextually salient subgroup anchors or, in some domains, the response-scale midpoint, than by population averages alone. These findings suggest that pluralistic ignorance may reflect a predictable structure in how normative perceptions are formed under uncertainty: perceived norms are organized around salient reference points and only partially adjusted in relation to individuals’ private attitudes.
