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Cellular trafficking between organelles is typically assured by short motifs that contact carrier proteins to transport them to their destination. The ubiquitin E3 ligase RING finger protein 13 (RNF13), a regulator of proliferation, apoptosis and protein trafficking, localizes to endolysosomal compartments through the binding of a dileucine motif to clathrin adaptor protein complex AP-3. Mutations within this motif reduce the ability ofRNF13 to interactwithAP-3. Here, our study shows the discovery of a glutamine-based motif that resembles a tyrosinebased motif within the C-terminal region of RNF13 that binds to the clathrin adaptor protein complex AP-1, notably without a functional interaction with AP-3. Using biochemical, molecular and cellular approaches in HeLa cells, our study demonstrates that a RNF13 dileucine variant uses anAP-1-dependent pathway to be exported from the Golgi towards the endosomal compartment. Overall, this study provides mechanistic insights into the alternate route used by this variant of the dileucine sorting motif of RNF13. [ABSTRACT FROM AUTHOR]

Background: Optic neuritis (ON) is a complex clinical syndrome that has diverse etiologies and treatments based on its subtypes. Notably, ON associated with multiple sclerosis (MS ON) has a good prognosis for recovery irrespective of treatment, whereas ON associated with other conditions including neuromyelitis optica spectrum disorders or myelin oligodendrocyte glycoprotein antibody–associated disease is often associated with less favorable outcomes. Delay in treatment of these non-MS ON subtypes can lead to irreversible vision loss. It is important to distinguish MS ON from other ON subtypes early, to guide appropriate management. Yet, identifying ON and differentiating subtypes can be challenging as MRI and serological antibody test results are not always readily available in the acute setting. The purpose of this study is to develop a deep learning artificial intelligence (AI) algorithm to predict subtype based on fundus photographs, to aid the diagnostic evaluation of patients with suspected ON. Methods: This was a retrospective study of patients with ON seen at our institution between 2007 and 2022. Fundus photographs (1,599) were retrospectively collected from a total of 321 patients classified into 2 groups: MS ON (262 patients; 1,114 photographs) and non-MS ON (59 patients; 485 photographs). The dataset was divided into training and holdout test sets with an 80%/20% ratio, using stratified sampling to ensure equal representation of MS ON and non-MS ON patients in both sets. Model hyperparameters were tuned using 5-fold cross-validation on the training dataset. The overall performance and generalizability of the model was subsequently evaluated on the holdout test set. Results: The receiver operating characteristic (ROC) curve for the developed model, evaluated on the holdout test dataset, yielded an area under the ROC curve of 0.83 (95% confidence interval [CI], 0.72–0.92). The model attained an accuracy of 76.2% (95% CI, 68.4–83.1), a sensitivity of 74.2% (95% CI, 55.9–87.4) and a specificity of 76.9% (95% CI, 67.6–85.0) in classifying images as non-MS–related ON. Conclusions: This study provides preliminary evidence supporting a role for AI in differentiating non-MS ON subtypes from MS ON. Future work will aim to increase the size of the dataset and explore the role of combining clinical and paraclinical measures to refine deep learning models over time. [ABSTRACT FROM AUTHOR]

Extracellular signal‐regulated kinase 3 (ERK3) is a poorly characterized member of the mitogen‐activated protein (MAP) kinase family. Functional analysis of the ERK3 signaling pathway has been hampered by a lack of knowledge about the substrates and downstream effectors of the kinase. Here, we used large‐scale quantitative phosphoproteomics and targeted gene silencing to identify direct ERK3 substrates and gain insight into its cellular functions. Detailed validation of one candidate substrate identified the gelsolin/villin family member supervillin (SVIL) as a bona fide ERK3 substrate. We show that ERK3 phosphorylates SVIL on Ser245 to regulate myosin II activation and cytokinesis completion in dividing cells. Depletion of SVIL or ERK3 leads to increased cytokinesis failure and multinucleation, a phenotype rescued by wild type SVIL but not by the non‐phosphorylatable S245A mutant. Our results unveil a new function of the atypical MAP kinase ERK3 in cell division and the regulation of cell ploidy. [ABSTRACT FROM AUTHOR]

Transition-type dwarf (TTD) galaxies share characteristics of early- and late-type dwarfs. Thus, they are suspected to be the thread that connects them. We selected 19 TTD galaxies in the nearby Universe (cz < 2900 km s−1) from the Sloan Digital Sky Survey. They span the luminosity range from ∼− 14.5 to −19.0 mag in the B band, and are located in different environments.We derive their single stellar population parameters and star formation histories, using the full spectrum fitting technique with two independent population synthesis models. Irrespective of the synthesis models, we find that these dwarfs have a relatively young mean age (around 1–2 Gyr) and low metallicities (∼− 0.7 dex). Moreover, they had approximately constant star formation rates until a few Gyr ago, associated with strong metal enrichment during the first few Gyr of their evolution. We compare these results with the results from Koleva et al., who studied dwarf elliptical (dE) galaxies in the same luminosity range. We find that (1) both samples occupy the same region in the luminosity–metallicity relation, (2) the build-up of the stellar mass in both types of galaxies is very similar, with most of the stars already formed 5 Gyr ago and (3) contrary to the dEs, TTDs are forming stars at present, but after 1 Gyr of passive evolution, their star formation histories would appear identical to that of dEs.As far as the stellar population is concerned, the transformation of TTDs into dEs is definitely possible. A star-forming dwarf galaxy can be stripped of at least a fraction of its gas, and its star formation rate can be reduced to that of the TTDs of the present sample. Continued gas removal may drive a galaxy to the state of a gas-depleted bona fide dE. However, we cannot exclude a scenario where a star-forming galaxy is rapidly transformed into an early type without passing through a noticeable ‘transition’ phase, as suggested by the relatively small fraction of observed dEs with an interstellar medium. We cannot exclude swinging back and forth between a late-type dwarf and a TTD (in the case of episodic star formation) or an early-type dwarf and a TTD (in the case of gas infall). [ABSTRACT FROM AUTHOR]