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Epigenetic gene silencing induced by expanded repeats can cause diverse phenotypes ranging from severe growth defects in plants to genetic diseases such as Friedreich's ataxia in humans. The molecular mechanisms underlying repeat expansion-induced epigenetic silencing remain largely unknown. Using a plant model with a temperature-sensitive phenotype, we have previously shown that expanded repeats can induce small RNAs, which in turn can lead to epigenetic silencing through the RNA-dependent DNA methylation pathway. Here, using a genetic suppressor screen and yeast two-hybrid assays, we identified novel components required for epigenetic silencing caused by expanded repeats. We show that FOURTH ULP GENE CLASS 1 (FUG1)-an uncharacterized SUMO protease with no known role in gene silencing-is required for epigenetic silencing caused by expanded repeats. In addition, we demonstrate that FUG1 physically interacts with ALFIN-LIKE 3 (AL3)-a histone reader that is known to bind to active histone mark H3K4me 2/3 . Loss of function of AL3 abolishes epigenetic silencing caused by expanded repeats. AL3 physically interacts with the chromodomain protein LIKE HETEROCHROMATIN 1 (LHP1)-known to be associated with the spread of the repressive histone mark H3K27me 3 to cause repeat expansion-induced epigenetic silencing. Loss of any of these components suppresses repeat expansion-associated phenotypes coupled with an increase in IIL1 expression with the reversal of gene silencing and associated change in epigenetic marks. Our findings suggest that the FUG1-AL3-LHP1 module is essential to confer repeat expansion-associated epigenetic silencing and highlight the importance of post-translational modifiers and histone readers in epigenetic silencing., (© 2024. The Author(s), under exclusive licence to Springer Nature Limited.) more...

The Authors report on the use of Flumazenil (Antagonist of the benzodiazepines in the CNS) in patients awakening from benzodiazepine induced necrosis for defibrillation. When used in these circumstances, the normal side effects of the narcosis (arrhythmia, rebound hypertensive convulsions, states of paradoxical anxiety) were almost completely absent. Furthermore, given the optimal quality of the rapid awakening, in about 5 minutes, the antagonistic qualities of the drug were confirmed making further development of the therapeutic uses of the benzodiazepines possible. more...

His bundle (HB) recording does not allow the recognition of third degree intrahisian block in patients with complete atrio-ventricular block (AVB) associated with idioventricular rhythm, due to the absence of pacemaker activation in the distal HB region. We have observed fixed retrograde distal HB activation in the standard HB recording of a patient with complete AVB and ventricular rhythm at a rate of 28/min. Retrograde distal HB activation (h'r) did not disappear during apical right ventricular pacing, in association with the complete absence of retrograde nodal conduction: concealed retroconduction into the proximal HB did not allow the recording of anterograde hisian deflection when the interval between h'r deflection and the subsequent sinus atriogram was shorter than 200 msec. Distal HB bipolar pacing using low energy stimulus resulted in 1:1 ventricular response and normal QRS duration in the absence of nodal retroconduction, thus proving the localization of bidirectional block within the HB. The unmasking of retrograde V-h' conduction during idioventricular rhythm was likely related to phase 4 retrograde delay in the branch ipsilateral to the site of the emergency ventricular focus and to the subsequent trans-septal activation of the other side of His-Purkinje system. Referring to arrhythmic problems after DDD pace-marker implantation the localization of complete AV blocks and retrograde conduction patterns are discussed. more...