We classify all non-invertible Kramers-Wannier duality defects in the E8 lattice Vertex Operator Algebra (i.e. the chiral (E8)1 WZW model) coming from ℤm symmetries. We illustrate how these defects are systematically obtainable as ℤ2 twists of invariant sub-VOAs, compute defect partition functions for small m, and verify our results against other techniques. Throughout, we focus on taking a physical perspective and highlight the important moving pieces involved in the calculations. Kac’s theorem for finite automorphisms of Lie algebras and contemporary results on holomorphic VOAs play a role. We also provide a perspective from the point of view of (2+1)d Topological Field Theory and provide a rigorous proof that all corresponding Tambara-Yamagami actions on holomorphic VOAs can be obtained in this manner. We include a list of directions for future studies.

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Background and RationaleAfter acute myocardial infarction (AMI), fibroblast activation protein (FAP) upregulation exceeds the infarct region. We sought further insights into the physiologic relevance by correlating FAP-targeted PET with tissue characteristics from cardiac magnetic resonance (CMR) and functional outcome. MethodsThirty-five patients underwent CMR, perfusion SPECT, and 68 Ga-FAPI-46 PET/CT within 11 days after AMI. Infarct size was determined from SPECT by comparison to reference database.For PET, regional standardized uptake values (SUV) and isocontour volumes-of-interest (VOI) determined the extent of cardiac FAP upregulation (FAP-volume). CMR yielded functional parameters, area of injury (late gadolinium enhancement, LGE) and T1/T2 mapping. Follow-up was available from echocardiography or CMR after 139.5 (IQR 80.5-188.25) days (n=14). ResultsThe area of FAP-upregulation was significantly larger than SPECT perfusion defect size (58±15 vs. 23±17%, p<0.001) and infarct area by LGE (28±11%, p<0.001). FAP-volume significantly correlated with CMR parameters at baseline (all p<0.001): infarct area (r=0.58), left ventricular (LV) mass (r=0.69), endsystolic (r=0.62) and enddiastolic volume (r=0.57). Segmental analysis revealed FAP-upregulation in 308/496 myocardial segments (62%). Significant LGE was found in only 56% of FAP-positive segments, elevated T1 in 74%, and elevated T2 in 68%. 14% (44/308) of FAP-positive segments exhibited neither prolonged T1 or T2 nor significant LGE. Of note, FAP-volume correlated only weakly with simultaneously measured left ventricular ejection fraction (LVEF) at baseline (r=-0.32, p=0.07), whereas there was a significant inverse correlation with LVEF obtained at later follow-up (r=-0.58, p=0.007).

Background: Immature neutrophils and HLA-DRneg/low monocytes expand in cancer, autoimmune diseases and viral infections, but their appearance and immunoregulatory effects on T-cells after acute myocardial infarction (AMI) remain underexplored.Methods and Results: We found an expansion of circulating immature CD16+CD66b+CD10neg neutrophils and CD14+HLA-DRneg/low monocytes in AMI patients, correlating with cardiac damage, function and levels of immune-inflammation markers. Immature CD10neg neutrophils expressed high amounts of MMP-9 and S100A9, and displayed resistance to apoptosis. Moreover, we found that increased frequency of CD10neg neutrophils and elevated circulating IFN-γ levels were linked, mainly in patients with expanded CD4+CD28null T-cells. Notably, the expansion of circulating CD4+CD28null T-cells was associated with cytomegalovirus (CMV) seropositivity. Using bioinformatic tools we identified a tight relationship among the peripheral expansion of immature CD10neg neutrophils, CMV IgG titers, and circulating levels of IFN-γ and IL-12 in patients with AMI. At a mechanistic level, CD10neg neutrophils enhanced IFN-γ production by CD4+ T-cells through a contact-independent mechanism involving IL-12. In vitro experiments also highlighted that HLA-DRneg/low monocytes do not suppress T-cell proliferation but secrete high levels of pro-inflammatory cytokines after differentiation to macrophages and IFN-γ stimulation. Lastly, using a mouse model of AMI, we showed that immature neutrophils (CD11bposLy6GposCD101neg cells) are recruited to the injured myocardium and migrate to mediastinal lymph nodes shortly after reperfusion.Conclusions: Immunoregulatory functions of CD10neg neutrophils play a dynamic role in mechanisms linking myeloid cell compartment dysregulation, Th1-type immune responses and inflammation after AMI.

Clopidogrel treatment in patients with coronary artery disease not only inhibits platelet activation but also improves endothelial function and nitric oxide (NO) bioavailability. Congestive heart failure (CHF) is associated with endothelial dysfunction and increased platelet activation. In rats with CHF following myocardial infarction (MI), we investigated whether treatment with clopidogrel modifies endothelial function. Eight weeks after coronary artery ligation, rats with CHF were randomized to placebo or the P2Y(12) receptor antagonist clopidogrel (5 mg/kg twice daily, given by gavage) for another 2 weeks. Afterwards, endothelial function was assessed in isolated aortic rings in organ bath experiments. Acetylcholine-induced, endothelium-dependent, nitric oxide-mediated vasorelaxation was significantly attenuated in CHF rats compared to sham-operated animals, and was significantly improved by treatment with clopidogrel. Adenosine-induced vasorelaxation via adenylyl cyclase stimulation was attenuated in CHF and significantly improved by clopidogrel. Increased vasoconstriction to phenylephrine was observed in CHF, particularly evident under cyclooxygenase inhibition, but prevented by clopidogrel treatment. Vasoconstriction by the P2Y(12) activator 2MeS-ADP was increased in CHF. Clopidogrel-treated CHF animals displayed enhanced phosphorylation of AKT and eNOS. In conclusion, clopidogrel improved endothelial function and NO bioavailability in heart failure. During CHF, sensitivity to P2Y(12) signaling was increased leading to impaired adenylyl cyclase-mediated signaling. Chronic P2Y(12)-blockade with clopidogrel improved adenylyl cyclase-mediated signaling including increased AKT- and eNOS-phosphorylation contributing to improved NO-mediated vasorelaxation.