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How RNA-binding proteins (RBPs) convey regulatory instructions to the core effectors of RNA processing is unclear. Here, we document the existence and functions of a multivalent RBP-effector interface. We show that the effector interface of a conserved RBP with an essential role in metazoan development, Unkempt, is mediated by a novel type of dual-purpose peptide motifs that can contact two different surfaces of interacting proteins. Unexpectedly, we find that the multivalent contacts do not merely serve effector recruitment but are required for the accuracy of RNA recognition by Unkempt. Systems analyses reveal that multivalent RBP-effector contacts can repurpose the principal activity of an effector for a different function, as we demonstrate for the reuse of the central eukaryotic mRNA decay factor CCR4-NOT in translational control. Our study establishes the molecular assembly and functional principles of an RBP-effector interface.

Development of new targeted inhibitors for oncogenic KRAS mutants may benefit from insight into how a given mutation influences the accessibility of protein residues and how compounds interact with mutant or wild-type KRAS proteins. Targeted proteomic analysis, a key validation step in the KRAS inhibitor development process, typically involves both intact mass- and peptide-based methods to confirm compound localization or quantify binding. However, these methods may not always provide a clear picture of the compound binding affinity for KRAS, how specific the compound is to the target KRAS residue, and how experimental conditions may impact these factors. To address this, we have developed a novel top-down proteomic assay to evaluate in vitro KRAS4B-compound engagement while assessing relative quantitation in parallel. We present two applications to demonstrate the capabilities of our assay: maleimide-biotin labeling of a KRAS4BG12D cysteine mutant panel and treatment of three KRAS4B proteins (WT, G12C, and G13C) with small molecule compounds. Our results show the time- or concentration-dependence of KRAS4B-compound engagement in context of the intact protein molecule while directly mapping the compound binding site.

BACKGROUND: Entrustable Professional Activities (EPA) and competencies represent components of a competency-based education framework. EPAs are assessed based on the level of supervision (LOS) necessary to perform the activity safely and effectively. The broad competencies, broken down into narrower subcompetencies, are assessed using milestones, observable behaviors of ones abilities along a developmental spectrum. Integration of the two methods, accomplished by mapping the most relevant subcompetencies to each EPA, may provide a cross check between the two forms of assessment and uncover those subcompetencies that have the greatest influence on the EPA assessment. OBJECTIVES: We hypothesized that 1) there would be a strong correlation between EPA LOS ratings with the milestone levels for the subcompetencies mapped to the EPA; 2) some subcompetencies would be more critical in determining entrustment decisions than others, and 3) the correlation would be weaker if the analysis included only milestones reported to the Accreditation Council for Graduate Medical Education (ACGME). METHODS: In fall 2014 and spring 2015, the Subspecialty Pediatrics Investigator Network asked Clinical Competency Committees to assign milestone levels to each trainee enrolled in a pediatric fellowship for all subcompetencies mapped to 6 Common Pediatric Subspecialty EPAs as well as provide a rating for each EPA based upon a 5-point LOS scale. RESULTS: One-thousand forty fellows were assessed in fall and 1048 in spring, representing about 27% of all fellows. For each EPA and in both periods, the average milestone level was highly correlated with LOS (rho range 0.59-0.74; p  0.05). CONCLUSIONS: We found a strong relationship between milestone level and EPA LOS rating but no difference if the subcompetencies were weighted, or if only milestones reported to the ACGME were used. Our results suggest that representative behaviors needed to effectively perform the EPA, such as key subcompetencies and milestones, allow for future language adaptations while still supporting the current model of assessment. In addition, these data provide additional validity evidence for using these complementary tools in building a program of assessment.

Operational agencies face significant challenges related to the verification and evaluation of weather forecasts. These challenges were investigated in a series of online workshops and polls engaging operational personnel from six countries. Five key themes emerged: inadequate verification approaches for both existing and emerging products; incomplete and uncertain observations; difficulties in accurately capturing users' real-world experiences using simplified metrics; poor communication and understanding of forecasts and complex verification information; and institutional factors such as limited resources, evolving meteorologist roles, and concerns over reputational damage. We identify nearly 50 operationally relevant scientific questions and suggest calls to action. Addressing these needs includes designing forecast systems with verification as a central consideration, enhancing the availability of observations, and developing and adopting community software systems. Additionally, we propose the establishment of an international community comprising environmental and social science researchers, statisticians, verification practitioners, and users to provide sustained support for this collective endeavor. KEYWORDS: Uncertainty; Forecast verification/skill; Numerical weather prediction/ forecasting; Operational forecasting; Communications/ decision-making, 1. Introduction Weather prediction (Fig. 1) is a continuously evolving enterprise. The rapid expansion of various types of data (including satellite and other kinds), coupled with increasing computer capabilities, advances [...]

Autologous T cells transduced to express a high affinity T-cell receptor specific to NY-ESO-1 (letetresgene autoleucel, lete-cel) show promise in the treatment of metastatic synovial sarcoma, with 50% overall response rate. The efficacy of lete-cel treatment in 45 synovial sarcoma patients (NCT01343043) has been previously reported, however, biomarkers predictive of response and resistance remain to be better defined. This post-hoc analysis identifies associations of response to lete-cel with lymphodepleting chemotherapy regimen (LDR), product attributes, cell expansion, cytokines, and tumor gene expression. Responders have higher IL-15 levels pre-infusion (p = 0.011) and receive a higher number of transduced effector memory (CD45RA- CCR7-) CD8 + cells per kg (p = 0.039). Post-infusion, responders have increased IFNγ, IL-6, and peak cell expansion (p

Black student activism in the 21st century has gained international notoriety with popular movements such as #StudentBlackOut, #FeesMustFall, and #ConcernedStudent1950 (Alfonzo & Foust, 2019; Turner, 2016). Between 2014 and 2017, Black students manipulated the momentum of a larger social movement--the Movement for Black Lives--in order to secure organizing victories for racial justice, both on and off their college campuses (Ransby, 2018; Williams, 2016). In this article, I explore the meaning-making processes of Black student activists who participated in on-campus or off-campus activism between 2014 and 2017. Themes from the interviews demonstrated that Black student activists were both politicized and entered movement organizing because of catalytic events, and that they saw themselves as resource brokers who funnel university resources, labor, and energy into dispossessed communities. In addition to arguing that participants used their racialized subjectivities to leverage resources and make changes for racial justice, I also assert that Black students were highly aware of their positionality; they raised critiques of their class-fluid positions as college students and the protections that their student identity provided them.

BackgroundAdvanced glycation end-products (AGE) are formed through nonenzymatic glycation of free amino groups in proteins or lipid. They are associated with inflammation and oxidative stress, and their accumulation in the body is implicated in chronic disease morbidity and mortality. We examined the association between postdiagnosis dietary Nε-carboxymethyl-lysine (CML)-AGE intake and mortality among women diagnosed with breast cancer.MethodsPostmenopausal women aged 50 to 79 years were enrolled in the Women's Health Initiative (WHI) between 1993 and 1998 and followed up until death or censoring through March 2018. We included 2,023 women diagnosed with first primary invasive breast cancer during follow-up who completed a food frequency questionnaire (FFQ) after diagnosis. Cox proportional hazards (PH) regression models estimated adjusted hazard ratios (HR) and 95% confidence intervals (CI) of association between tertiles of postdiagnosis CML-AGE intake and mortality risk from all causes, breast cancer, and cardiovascular disease.ResultsAfter a median 15.1 years of follow-up, 630 deaths from all causes were reported (193 were breast cancer-related, and 129 were cardiovascular disease-related). Postdiagnosis CML-AGE intake was associated with all-cause (HRT3vsT1, 1.37; 95% CI, 1.09-1.74), breast cancer (HRT3vsT1, 1.49; 95% CI, 0.98-2.24), and cardiovascular disease (HRT3vsT1, 1.91; 95% CI, 1.09-3.32) mortality.ConclusionsHigher intake of AGEs was associated with higher risk of major causes of mortality among postmenopausal women diagnosed with breast cancer.ImpactOur findings suggest that dietary AGEs may contribute to the risk of mortality after breast cancer diagnosis. Further prospective studies examining dietary AGEs in breast cancer outcomes and intervention studies targeting dietary AGE reduction are needed to confirm our findings.

Substantial abundance and diversity of intertidal invertebrates known as meiofauna are evident on a sandy beach of Sapelo Island, Georgia. Meiofauna are small, benthic, nearly ubiquitous animals. They consume microbes and detritus and are a food source for juvenile fish and ghost shrimp. Meiofauna were manually separated from sand samples collected from three intertidal zones and two depths during low tide in January, March, June, and October, 2017. Fifteen major meiofaunal taxonomic groups were identified in June, while only eight were observed in January; in all, there were sixteen groups observed. Highest meiofauna densities were found in the middle intertidal zone and in the top 5 cm of sand. Abundance was high year-round, and highest in the summer and fall months. Temperature, sand grain size, slope of the beach, and weathering processes may influence this meiofaunal variation. This research could contribute future insight into metazoan food webs and beach disturbances. KEYWORDS Meiofauna; beach; nematode; intertidal; Sapelo Island, INTRODUCTION Exposed sandy beaches contain a diverse and abundant meiofaunal community (Brown and McLachlan 1990). Meiofauna are defined as organisms ranging in size from 50 - 500 micrometers that live [...]