NF90/NFAR (nuclear factors associated with dsRNA) - a new methylation substrate of the PRMT5-WD45-RioK1 complex.

Protein-arginine methylation is a common posttranslational modification, crucial to various cellular processes, such as protein-protein interactions or binding to nucleic acids. The central enzyme of symmetric protein arginine methylation in mammals is the protein arginine methyltransferase 5 (PRMT5). While the methylation reaction itself is well understood, recruitment and differentiation among substrates remain less clear. One mechanism to regulate the diversity of PRMT5 substrate recognition is the mutual binding to the adaptor proteins pICln or RioK1. Here, we describe the specific interaction of Nuclear Factor 90 (NF90) with the PRMT5-WD45-RioK1 complex. We show for the first time that NF90 is symmetrically dimethylated by PRMT5 within the RG-rich region in its C-terminus. Since upregulation of PRMT5 is a hallmark of many cancer cells, the characterization of its dimethylation and modulation by specific commercial inhibitors in vivo presented here may contribute to a better understanding of PRMT5 function and its role in cancer.

Evaluation of a Digital Self-management Platform for Patients With Chronic Illness in Primary Care: Qualitative Study of Stakeholders' Perspectives.

BACKGROUND: Population aging and multimorbidity has led to increasing chronic care needs associated with new challenges in managing growing costs, rising health care professional workloads, and the adoption of rigorous guidelines. These issues could all benefit from greater digitalization and a more patient-centered approach to chronic care, a situation brought to the fore by the COVID-19 pandemic. Little is known about real-life use in primary care. OBJECTIVE: This study aimed to explore the views, thoughts, usability, and experiences concerning a recently introduced digital self-care platform for chronic conditions in 3 Dutch primary care practices. METHODS: We conducted an explorative study combining questionnaires and interviews among patients and general practitioners from 3 general practices that used the digital platform. Questionnaires were sent to patients in each practice to seek the views and experiences of both patient nonusers (n=20) and patient users (n=58) of the platform, together with standardized questionnaires about illness perception and quality of life. In addition, patients (n=15) and general practitioners (n=4) who used the platform took part in semistructured interviews. We transcribed interviews verbatim and performed qualitative content analysis using a deductive approach. The results of the questionnaires were analyzed with descriptive analysis. RESULTS: Among patients who had not actively used the platform but had received an explanation, only 35% (7/20) would recommend its use due to concerns over communication and handling. However, this percentage increased to 76.3% (45/59) among the people who actively used the platform. Interviews with patients and general practitioners who used the platform uncovered several key benefits, including reduced time requirements, reduced workload, improved care quality, and improved accessibility due to the greater patient-centeredness and use of different communication tools. In addition, the self-management tool led to greater patient autonomy and empowerment. Although users considered the platform feasible, usable, and easy to use, some technical issues remained and some patients expressed concerns about the reduction in human contact and feedback. CONCLUSIONS: The overall experience and usability of the platform was good. Support for the online self-management platform for chronic care increased when patients actively used the tool and could experience or identify important advantages. However, patients still noted several areas for improvement that need to be tackled in future iterations. To ensure benefit in the wider population, we must also evaluate this platform in cohorts with lower digital and health literacy.

An essential role of the autophagy activating kinase ULK1 in snRNP biogenesis.

The biogenesis of small uridine-rich nuclear ribonucleoproteins (UsnRNPs) depends on the methylation of Sm proteins catalyzed by the methylosome and the subsequent action of the SMN complex, which assembles the heptameric Sm protein ring onto small nuclear RNAs (snRNAs). In this sophisticated process, the methylosome subunit pICln (chloride conductance regulatory protein) is attributed to an exceptional key position as an 'assembly chaperone' by building up a stable precursor Sm protein ring structure. Here, we show that-apart from its autophagic role-the Ser/Thr kinase ULK1 (Uncoordinated [unc-51] Like Kinase 1) functions as a novel key regulator in UsnRNP biogenesis by phosphorylation of the C-terminus of pICln. As a consequence, phosphorylated pICln is no longer capable to hold up the precursor Sm ring structure. Consequently, inhibition of ULK1 results in a reduction of efficient UsnRNP core assembly. Thus ULK1, depending on its complex formation, exerts different functions in autophagy or snRNP biosynthesis.

TNF-induced necroptosis initiates early autophagy events via RIPK3-dependent AMPK activation, but inhibits late autophagy.

Macroautophagy/autophagy and necroptosis represent two opposing cellular s tress responses. Whereas autophagy primarily fulfills a cyto-protective function, necroptosis is a form of regulated cell death induced via death receptors. Here, we aimed at investigating the molecular crosstalk between these two pathways. We observed that RIPK3 directly associates with AMPK and phosphorylates its catalytic subunit PRKAA1/2 at T183/T172. Activated AMPK then phosphorylates the autophagy-regulating proteins ULK1 and BECN1. However, the lysosomal degradation of autophagosomes is blocked by TNF-induced necroptosis. Specifically, we observed dysregulated SNARE complexes upon TNF treatment; e.g., reduced levels of full-length STX17. In summary, we identified RIPK3 as an AMPK-activating kinase and thus a direct link between autophagy- and necroptosis-regulating kinases.Abbreviations: ACACA/ACC: acetyl-CoA carboxylase alpha; AMPK: AMP-activated protein kinase; ATG: autophagy-related; BECN1: beclin 1; GFP: green fluorescent protein; EBSS: Earle's balanced salt solution; Hs: Homo sapiens; KO: knockout; MAP1LC3/LC3: microtubule associated protein 1 light chain 3; MEF: mouse embryonic fibroblast; MLKL: mixed lineage kinase domain like pseudokinase; Mm: Mus musculus; MTOR: mechanistic target of rapamycin kinase; MVB: multivesicular body; PIK3C3/VPS34: phosphatidylinositol 3-kinase catalytic subunit type 3; PIK3R4/VPS15: phosphoinositide-3-kinase regulatory subunit 4; PLA: proximity ligation assay; PRKAA1: protein kinase AMP-activated catalytic subunit alpha 1; PRKAA2: protein kinase AMP-activated catalytic subunit alpha 2; PRKAB2: protein kinase AMP-activated non-catalytic subunit beta 2; PRKAG1: protein kinase AMP-activated non-catalytic subunit gamma 1; PtdIns3K: phosphatidylinositol 3-kinase; PtdIns3P: phosphatidylinositol-3-phosphate; RIPK1: receptor interacting serine/threonine kinase 1; RIPK3: receptor interacting serine/threonine kinase 3; SNAP29: synaptosome associated protein 29; SNARE: soluble N-ethylmaleimide-sensitive factor attachment protein receptor; SQSTM1/p62: sequestosome 1; STK11/LKB1: serine/threonine kinase 11; STX7: syntaxin 7; STX17: syntaxin 17; TAX1BP1: Tax1 binding protein 1; TNF: tumor necrosis factor; ULK1: unc-51 like autophagy activating kinase 1; VAMP8: vesicle associated membrane protein 8; WT: wild-type.

The Autophagy-Initiating Kinase ULK1 Controls RIPK1-Mediated Cell Death.

Autophagy, apoptosis, and necroptosis are stress responses governing the ultimate fate of a cell. However, the crosstalk between these cellular stress responses is not entirely understood. Especially, it is not clear whether the autophagy-initiating kinase ULK1 and the cell-death-regulating kinase RIPK1 are involved in this potential crosstalk. Here, we identify RIPK1 as a substrate of ULK1. ULK1-dependent phosphorylation of RIPK1 reduces complex IIb/necrosome assembly and tumor necrosis factor (TNF)-induced cell death, whereas deprivation of ULK1 enhances TNF-induced cell death. We observe that ULK1 phosphorylates multiple sites of RIPK1, but it appears that especially phosphorylation of S357 within the intermediate domain of RIPK1 mediates this cell-death-inhibiting effect. We propose that ULK1 is a regulator of RIPK1-mediated cell death.

Identifying Barriers to Building a Diverse Physician Workforce: A National Survey of the ACR Membership.

PURPOSE: The aim of this study was to identify potential barriers to building a diverse workforce in radiology and radiation oncology by conducting a national survey of physicians in these fields and studying their reported career experiences. METHODS: An electronic survey of ACR members (February 27, 2018, to April 26, 2018) was conducted in which physicians' attitudes about their work environment, relationships, and culture were queried. The aim was to determine if responses differed by gender or race/ethnicity. In total, 900 invitations were issued; women were oversampled with the goal of equal representation. Descriptive summaries (proportions of yes or no responses) were calculated per item, per subgroup of interest. Logistic regression analysis was used to identify significant associations between gender- and item-specific responses; it was not used in the race/ethnicity analysis because of the small sizes of many subgroups. RESULTS: The response rate was 51.2% (461 of 900). In total, 51.0% of respondents identified as women (235 of 461); the 9.5% (44 of 461) who identified as black or African American, Hispanic, or American Indian or Alaska Native were considered underrepresented minorities. Respondents' mean age was 40.2 ± 10.4 years. Subgroups varied most in their reporting of unfair or disrespectful treatment. Women were significantly more likely than men to report such treatment attributable to gender (50.6% versus 5.4%; odds ratio, 18.00; 95% confidence interval, 9.29-34.86; P < .001), and 27.9% of underrepresented minorities compared with 2.6% of white non-Hispanic respondents reported such treatment attributable to race/ethnicity. CONCLUSIONS: Women and underrepresented minorities disproportionately experience unfair or disrespectful treatment in the workplace. Addressing this problem is likely to be critically important for improving workforce diversity.

The 2015 ACR Commission on Human Resources Workforce Survey.

PURPOSE: The ACR Commission on Human Resources continues to conduct its annual electronic survey to better understand the present workforce scenario for radiologists. METHODS: The Practice of Radiology Environment Database was used to identify group leads, who were asked to complete an electronic survey developed by the Commission on Human Resources. The survey asked group leaders to report the number of radiologists they currently employ or supervise, the number hired in 2014, and the numbers they plan to hire in 2015 and 2018. The leaders were asked to report the subspecialty area used as the main reason for hiring each physician, as well as the ages and genders of their current workforce. RESULTS: Thirty-two percent of group leaders responded to the survey, corresponding to 12,079 radiologists or 39% of all practicing radiologists. Twenty-one percent of the workforce is female and 79% is male. Ten percent of radiologists older than 65 years are women, while 32% younger than 35 are women. Twelve percent of radiologists work part-time, corresponding to a breakdown of 10% of men and 24% of women working part-time. The current workforce is 13% general radiologists and 87% subspecialists. In 2015, a projected 1,131 to 1,484 jobs will be available for radiologists. CONCLUSIONS: Job opportunities for radiologists seem to be increasing compared with 2013 and are relatively similar to 2014. Radiologists continue to subspecialize in greater numbers, but only 39% of radiologists practice more than 50% of the time in their subspecialties.

When does expert witness testimony constitute a violation of the ACR Code of Ethics? The role of the ACR Committee on Ethics.

The ACR established the Committee on Ethics in 1997. As outlined in a prior article in JACR, the committee reviews allegations that an ACR member violated the Code of Ethics. One type of complaint is that an ACR member provided biased or inaccurate expert medical testimony. This article describes how the committee reviews expert witness complaints, decides whether to investigate them, and in some cases imposes disciplinary sanctions against a member.