JAZF1: A metabolic actor subunit of the NuA4/TIP60 chromatin modifying complex

The multisubunit NuA4/TIP60 complex is a lysine acetyltransferase, chromatin modifying factor and gene co-activator involved in diverse biological processes. The past decade has seen a growing appreciation for its role as a metabolic effector and modulator. However, molecular insights are scarce and often contradictory, underscoring the need for further mechanistic investigation. A particularly exciting route emerged with the recent identification of a novel subunit, JAZF1, which has been extensively linked to metabolic homeostasis. This review summarizes the major findings implicating NuA4/TIP60 in metabolism, especially in light of JAZF1 as part of the complex

Impact of negative inotropic drugs on accuracy of diastolic stress echocardiography for evaluation of left ventricular filling pressure

Abstract The ratio of early diastolic trans-mitral flow velocity to tissue-Doppler mitral annular early diastolic velocity (E/e′), and left ventricular end-diastolic pressure(LVEDP) have been shown to be correlated at rest, provided that patients are not on positive inotropic drugs. Data concerning the latter correlation during exercise stress are conflicting. Therefore, we investigated if use of negative inotropic drugs (NID), impacts the accuracy of E/e′ as a surrogate for LVEDP during low-level exercise. An exercise(50 watts) during cardiac invasive hemodynamic monitoring and an exercise echocardiography were performed prospectively within 24 hours in 54 patients (81%male, 62 ± 9years) with preserved LV Ejection-Fraction. Before exercise, the patients had scattered LVEDP (13.8 ± 5.8 mmHg) and septal E/e′ (8.7 ± 2.7). Half of them were on NID, mainly betablockers(n = 26). The correlation between septal-E/e′ and LVEDP was low for examinations performed at rest (r = 0.35,p = 0.01) with no significant impact of NID. For measurements performed at 50 Watts, NID had a significant impact on the association between septal-E/e′50 watts and LVEDP50 watts (β = −0.28,p = 0.03). Correlation between septal-E/e′50 watts and LVEDP50 watts persisted in patients on NID (r = 0.61,p = 0.001) while it disappeared in the group of patients with no NID (r = 0.15,p = 0.47). NID use is an important confounding factor to take into consideration when assessing exercise LVFP using stress E/e′ in patients with preserved LVEF

Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

BackgroundWe previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in similar to 80% of cases.MethodsWe report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.ResultsNo gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P=1.1x10(-4)) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR=3.70[95%CI 1.3-8.2], P=2.1x10(-4)). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR=19.65[95%CI 2.1-2635.4], P=3.4x10(-3)), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR=4.40[9%CI 2.3-8.4], P=7.7x10(-8)). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD]=43.3 [20.3] years) than the other patients (56.0 [17.3] years; P=1.68x10(-5)).ConclusionsRare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old

Correction: Rare predicted loss-of-function variants of type I IFN immunity genes are associated with life-threatening COVID-19

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