Slx5/Slx8-dependent ubiquitin hotspots on chromatin contribute to stress tolerance

Chromatin is a highly regulated environment, and protein association with chromatin is often controlled by post-translational modifications and the corresponding enzymatic machinery. Specifically, SUMO-targeted ubiquitin ligases (STUbLs) have emerged as key players in nuclear quality control, genome maintenance, and transcription. However, how STUbLs select specific substrates among myriads of SUMOylated proteins on chromatin remains unclear. Here, we reveal a remarkable co-localization of the budding yeast STUbL Slx5/Slx8 and ubiquitin at seven genomic loci that we term "ubiquitin hotspots". Ubiquitylation at these sites depends on Slx5/Slx8 and protein turnover on the Cdc48 segregase. We identify the transcription factor-like Ymr111c/Euc1 to associate with these sites and to be a critical determinant of ubiquitylation. Euc1 specifically targets Slx5/Slx8 to ubiquitin hotspots via bipartite binding of Slx5 that involves the Slx5 SUMO-interacting motifs and an additional, novel substrate recognition domain. Interestingly, the Euc1-ubiquitin hotspot pathway acts redundantly with chromatin modifiers of the H2A.Z and Rpd3L pathways in specific stress responses. Thus, our data suggest that STUbL-dependent ubiquitin hotspots shape chromatin during stress adaptation

Comprehensive design and whole-cavity simulation of a multi-beam inductive output tube using a 3rd harmonic drive on the grid

In this paper, we discuss the design and whole-cavity simulation of a Multi-Beam Inductive Output Tube (MBIOT) that uses a 3rd harmonic component to the drive voltage on the grid. High-efficiency inductive output tubes (IOTs) are typically characterized by efficiencies up to 70 - 75%. However, the achievement of efficiencies greater than 80% would substantially reduce the operating costs of next-generation accelerators. To achieve this goal, we consider the addition of a 3rd harmonic component to the drive signal on the grid. We anticipate that the MBIOT will be used to provide the rf power to drive RF linacs. We discuss and model an 8-beam MBIOT with a 700 MHz resonant cavity using beams with a voltage of 35 kV and an average current of 7.25 A yielding a perveance of about 1.1 microP. We simulate this MBIOT using the NEMESIS simulation code which has been extended using a three-dimensional Poisson solver based upon the Petsc package from Argonne National Laboratory. The effect of the 3rd harmonic on the efficiency is greatest when the phase of the 3rd harmonic is shifted by pi radians with respect to the fundamental drive signal and with 3rd harmonic powers greater than about 50% of the fundamental drive power. For the present example, we show that efficiencies approaching 82% are possible. Designs for the MBIOT input coupler, grids and output cavity have been developed based on these simulations and will be discussed.Comment: 12 pages, 30 figure

Task difficulty and life changes among stroke family caregivers: relationship to depressive symptoms

OBJECTIVES: To investigate differences in stroke caregiver task difficulty and life changes based on level of caregiver depressive symptoms, and to estimate probabilities among task difficulty and life change items. DESIGN: Descriptive analysis of baseline data from an ongoing stroke caregiver intervention trial. SETTING: Hospitals and rehabilitation facilities. PARTICIPANTS: Caregivers (N=242; 78.6% women; 47.7% spouses; 71.8% white; mean age, 54.2±12.1y) caring for stroke survivors within 8 weeks of discharge to home. INTERVENTIONS: Not applicable. MAIN OUTCOME MEASURES: Baseline measures for task difficulty (Oberst Caregiving Burden Scale) and life changes (Bakas Caregiving Outcomes Scale) were compared based on level of depressive symptoms (Patient Health Questionnaire-9 [PHQ-9] scores <5 means no depressive symptoms; n=126; PHQ-9 scores ≥5 means mild to severe depressive symptoms, n=116). Mean scores were analyzed using general linear modeling, with item analyses using logistic regression and the Benjamini-Hochberg method to control type I error inflation. RESULTS: Caregivers with mild to severe depressive symptoms have greater difficulty with tasks and worse life changes than those with no depressive symptoms (P<.001). Odds ratios were highest for the task of arranging care while away and for negative life changes (eg, addressing self-esteem, coping with stress, physical health). CONCLUSIONS: Findings underscore the importance of depressive symptom screening for stroke caregivers during or shortly after discharge. Assisting caregivers with depressive symptoms to arrange for respite care and addressing negative physical and psychological changes may be priority areas for future interventions