SUMMARY TRIM58 is an E3 ubiquitin ligase superfamily member implicated by genome wide association studies (GWAS) to regulate human erythrocyte traits. Here we show that Trim58 expression is induced during late erythropoiesis and that its depletion by shRNAs inhibits the maturation of late stage nucleated erythroblasts to anucleate reticulocytes. Imaging flow cytometry studies demonstrate that Trim58 regulates polarization and/or extrusion of erythroblast nuclei. In vitro, Trim58 directly binds and ubiquitinates the intermediate chain of the microtubule motor dynein. In cells, Trim58 stimulates proteasome-dependent degradation of the dynein holoprotein complex. During erythropoiesis, Trim58 expression, dynein loss and enucleation occur concomitantly and all are inhibited by Trim58 shRNAs. Dynein regulates nuclear positioning and microtubule organization, both of which undergo dramatic changes during erythroblast enucleation. Thus, we propose that Trim58 regulates this process by eliminating dynein. Our findings identify an erythroid-specific regulator of enucleation and elucidate a previously unrecognized mechanism for controlling dynein activity.
BackgroundHemodialysis is associated with a high symptom burden that impairs health-related quality of life and functional status. Effective symptom management is a priority for individuals receiving hemodialysis. Aerobic exercise may be an effective, nonpharmacologic treatment for specific hemodialysis-related symptoms. This systematic review investigated the effect of aerobic exercise on hemodialysis-related symptoms in adults with kidney failure undergoing maintenance hemodialysis.Design, setting, participants, & measurementsWe searched MEDLINE, PubMed, Cochrane CENTRAL, CINAHL, PsycINFO, SPORTDiscus, EMBASE, PEDro, and Scopus databases from 1960 or inception until April 15, 2020 for randomized controlled trials investigating the effect of aerobic exercise on hemodialysis-related symptoms, identified as prespecified primary or secondary outcomes, as compared with controls in adults on maintenance hemodialysis. We identified restless legs syndrome as the primary outcome.ResultsOf 3048 studies identified, 15 randomized controlled trials met the eligibility criteria. These studies investigated the effect of aerobic exercise on restless legs syndrome (two studies), sleep disturbance (four studies), anxiety (four studies), depression (nine studies), muscle cramping (one study), and fatigue (one study). Exercise interventions were intradialytic in ten studies and outside of hemodialysis in five studies. Heterogenous interventions and outcomes and moderate to high risk of bias precluded meta-analysis for most symptoms. Aerobic exercise demonstrated improvement in symptoms of restless legs syndrome, muscle cramping, and fatigue, as compared with nonexercise controls. Meta-analysis of depressive symptoms in studies using the Beck Depression Inventory demonstrated a greater reduction in Beck Depression Inventory score with exercise as compared with control (mean difference −7.57; 95% confidence interval, −8.25 to −6.89).ConclusionsOur review suggests that in adults on maintenance hemodialysis, aerobic exercise improves several hemodialysis-related symptoms, including restless legs syndrome, symptoms of depression, muscle cramping, and fatigue. However, the use of validated outcome measures with demonstrated reliability and responsiveness in more diverse hemodialysis populations is required to fully characterize the effect of this intervention.Clinical Trial registry name and registration number:PROSPERO #CRD42017056658
Purpose:Quality of life (QOL) for patients with oropharyngeal squamous cell cancer is negatively affected by conventional radiation (RT) owing to radiation exposure to normal tissues. Proton therapy, via pencil beam scanning (PBS), can better spare many of these tissues, and may thereby improve QOL.Patients and Methods:Patient-reported outcomes were prospectively collected from patients treated from April 2013 to April 2015. Patients were treated with PBS or intensity-modulated radiation therapy (IMRT) via volumetric arc therapy after transoral robotic surgery. Validated QOL questionnaires were collected before RT, and 3, 6, and 12 months post RT.Results:Sixty-four patients were treated with adjuvant RT after transoral robotic surgery, 33 (52%) with volumetric arc therapy, and 31 (48%) with PBS. Both groups were similar in terms of age, site, stage, and dose delivered. Patients receiving PBS had significantly less dose to many normal structures than those receiving IMRT. These dosimetric advantages with PBS were reflected in higher scores in head and neck specific, as well as general, QOL measures. Most notable was significantly less xerostomia with PBS, on multiple patient-reported outcomes at multiple timepoints (6 and 12 months).Conclusion:Pencil beam scanning, when compared to IMRT, confers a significant dosimetric advantage to many normal organs at risk, with a corresponding benefit in multiple patient-reported QOL parameters in patients receiving adjuvant RT for oropharyngeal squamous cell cancer.
The regenerative potential of brain stem cell niches deteriorates during aging. Yet the mechanisms underlying this decline are largely unknown. Here we characterize genome-wide chromatin accessibility of neurogenic niche cells in vivo during aging. Interestingly, chromatin accessibility at adhesion and migration genes decreases with age in quiescent neural stem cells (NSCs) but increases with age in activated (proliferative) NSCs. Quiescent and activated NSCs exhibit opposing adhesion behaviors during aging: quiescent NSCs become less adhesive, whereas activated NSCs become more adhesive. Old activated NSCs also show decreased migration in vitro and diminished mobilization out of the niche for neurogenesis in vivo. Using tension sensors, we find that aging increases force-producing adhesions in activated NSCs. Inhibiting the cytoskeletal-regulating kinase ROCK reduces these adhesions, restores migration in old activated NSCs in vitro, and boosts neurogenesis in vivo. These results have implications for restoring the migratory potential of NSCs and for improving neurogenesis in the aged brain.
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