The UFM1 E3 ligase recognizes and releases 60S ribosomes from ER translocons.

Stalled ribosomes at the endoplasmic reticulum (ER) are covalently modified with the ubiquitin-like protein UFM1 on the 60S ribosomal subunit protein RPL26 (also known as uL24). This modification, which is known as UFMylation, is orchestrated by the UFM1 ribosome E3 ligase (UREL) complex, comprising UFL1, UFBP1 and CDK5RAP3 (ref. ).

Acute depletion of the ARID1A subunit of SWI/SNF complexes reveals distinct pathways for activation and repression of transcription.

The ARID1A subunit of SWI/SNF chromatin remodeling complexes is a potent tumor suppressor. Here, a degron is applied to detect rapid loss of chromatin accessibility at thousands of loci where ARID1A acts to generate accessible minidomains of nucleosomes. Loss of ARID1A also results in the redistribution of the coactivator EP300.

Non-epistemic values in shaping the parameters for evaluating the effectiveness of candidate vaccines: the case of an Ebola vaccine trial.

This paper examines the case of Ebola, ça Suffit trial which was conducted in Guinea during Ebola Virus Disease (EVD) outbreak in 2015. I demonstrate that various non-epistemic considerations may legitimately influence the criteria for evaluating the efficacy and effectiveness of a candidate vaccine. Such non-epistemic considerations, which are social, ethical, and pragmatic, can be better placed and addressed in scientific research by appealing to non-epistemic values.

Phosphorylation of NANOG by casein kinase I regulates embryonic stem cell self-renewal.

The self-renewal efficiency of mouse embryonic stem cells (ESCs) is determined by the concentration of the transcription factor NANOG. While NANOG binds thousands of sites in chromatin, the regulatory systems that control DNA binding are poorly characterised. Here, we show that NANOG is phosphorylated by casein kinase I, and identify target residues.

Characterisation of the biochemical and cellular roles of native and pathogenic amelogenesis imperfecta mutants of FAM83H.

The majority of mutations identified in patients with amelogenesis imperfecta have been mapped to FAM83H. As FAM83H expression is not limited to the enamel, how FAM83H contributes to amelogenesis is still largely unknown. We previously reported that members of the FAM83 family of proteins interact with and regulate the subcellular distribution of the promiscuous serine-threonine protein kinase CK1 family, through their shared N-terminal DUF1669 domains.

Genetic recoding to dissect the roles of site-specific protein O-GlcNAcylation.

Modification of specific Ser and Thr residues of nucleocytoplasmic proteins with O-GlcNAc, catalyzed by O-GlcNAc transferase (OGT), is an abundant posttranslational event essential for proper animal development and is dysregulated in various diseases. Due to the rapid concurrent removal by the single O-GlcNAcase (OGA), precise functional dissection of site-specific O-GlcNAc modification in vivo is currently not possible without affecting the entire O-GlcNAc proteome. Exploiting the fortuitous promiscuity of OGT, we show that S-GlcNAc is a hydrolytically stable and accurate structural mimic of O-GlcNAc that can be encoded in mammalian systems with CRISPR-Cas9 in an otherwise unperturbed O-GlcNAcome.

Pathogenic palmoplantar keratoderma mutations inhibit the PAWS1:CK1α association and attenuate Wnt signalling.

Two recessive mutations in the gene, causing A34E and R52P amino acid substitutions in the DUF1669 domain of the PAWS1 protein, are associated with palmoplantar keratoderma (PPK) in humans and dogs respectively. We have previously reported that PAWS1 associates with the Ser/Thr protein kinase CK1α through the DUF1669 domain to mediate canonical Wnt signalling. Co-immunoprecipitation was used to investigate possible changes to PAWS1 interactors caused by the mutations.

FAM83D directs protein kinase CK1α to the mitotic spindle for proper spindle positioning.

The concerted action of many protein kinases helps orchestrate the error-free progression through mitosis of mammalian cells. The roles and regulation of some prominent mitotic kinases, such as cyclin-dependent kinases, are well established. However, these and other known mitotic kinases alone cannot account for the extent of protein phosphorylation that has been reported during mammalian mitosis.

Philosophical import of non-epistemic values in clinical trials and data interpretation.

In this essay, I argue that at least in two phases of pharmaceutical research, especially while assessing the adequacy of the accumulated data and its interpretation, the influence of non-epistemic values is necessary. I examine a specific case from the domain of pharmaceutical research and demonstrate that there are multiple competing sets of values which may legitimately or illegitimately influence different phases of the inquiry. In such cases, the choice of the appropriate set of values-epistemic as well as non-epistemic-should be made on the basis of the set's viability to promote specific epistemic and social aims of the research, in the case at hand, rather than other competing aims.

Outcomes related to immediate extubation after stage 1 Norwood palliation for hypoplastic left heart syndrome.

Objective: Immediate extubation may have outcome benefits when judiciously instituted after neonatal congenital cardiac surgery. We sought to evaluate the outcomes of immediate extubation specifically in neonates undergoing stage 1 Norwood palliation of hypoplastic left heart syndrome.

Methods: Consecutive neonates undergoing stage 1 Norwood (January 2010 to December 2016) for hypoplastic left heart syndrome were retrospectively studied.

The DUF1669 domain of FAM83 family proteins anchor casein kinase 1 isoforms.

Members of the casein kinase 1 (CK1) family of serine-threonine protein kinases are implicated in the regulation of many cellular processes, including the cell cycle, circadian rhythms, and Wnt and Hedgehog signaling. Because these kinases exhibit constitutive activity in biochemical assays, it is likely that their activity in cells is controlled by subcellular localization, interactions with inhibitory proteins, targeted degradation, or combinations of these mechanisms. We identified members of the FAM83 family of proteins as partners of CK1 in cells.

PAWS1 controls Wnt signalling through association with casein kinase 1α.

The BMP and Wnt signalling pathways determine axis specification during embryonic development. Our previous work has shown that PAWS1 (also known as FAM83G) interacts with SMAD1 and modulates BMP signalling. Here, surprisingly, we show that overexpression of PAWS1 in embryos activates Wnt signalling and causes complete axis duplication.

PAWS1 controls cytoskeletal dynamics and cell migration through association with the SH3 adaptor CD2AP.

Our previous studies of PAWS1 (protein associated with SMAD1; also known as FAM83G) have suggested that this molecule has roles beyond BMP signalling. To investigate these roles, we have used CRISPR/Cas9 to generate PAWS1-knockout U2OS osteosarcoma cells. Here, we show that PAWS1 plays a role in the regulation of the cytoskeletal machinery, including actin and focal adhesion dynamics, and cell migration.

Five-year experience with immediate extubation after arterial switch operations for transposition of great arteries.

Objectives: We sought to identify preoperative, intraoperative and anatomical factors associated with immediate extubation (IE) after arterial switch operation for d-transposition of great arteries (dTGA).

Methods: This was a single-centre retrospective study performed from 1 January 2010 to 30 June 2015. IE was defined as successful extubation in the operating room (OR).

Functional kinomics establishes a critical node of volume-sensitive cation-Cl cotransporter regulation in the mammalian brain.

Cell volume homeostasis requires the dynamically regulated transport of ions across the plasmalemma. While the ensemble of ion transport proteins involved in cell volume regulation is well established, the molecular coordinators of their activities remain poorly characterized. We utilized a functional kinomics approach including a kinome-wide siRNA-phosphoproteomic screen, a high-content kinase inhibitor screen, and a kinase trapping-Orbitrap mass spectroscopy screen to systematically identify essential kinase regulators of KCC3 Thr/Thr phosphorylation - a key signaling event in cell swelling-induced regulatory volume decrease (RVD).

Preoperative and Intraoperative Predictive Factors of Immediate Extubation After Neonatal Cardiac Surgery.

Background: We sought to identify preoperative and intraoperative predictors of immediate extubation (IE) after open heart surgery in neonates. The effect of IE on the postoperative intensive care unit (ICU) length of stay (LOS), cost of postoperative ICU care, operating room turnover, and reintubation rates was assessed.

Methods: Patients younger than 31 days who underwent cardiac surgery with cardiopulmonary bypass (January 2010 to December 2013) at a tertiary-care children's hospital were studied.

UBQLN2 Mediates Autophagy-Independent Protein Aggregate Clearance by the Proteasome.

Clearance of misfolded and aggregated proteins is central to cell survival. Here, we describe a new pathway for maintaining protein homeostasis mediated by the proteasome shuttle factor UBQLN2. The 26S proteasome degrades polyubiquitylated substrates by recognizing them through stoichiometrically bound ubiquitin receptors, but substrates are also delivered by reversibly bound shuttles.

Outcomes and Perception of a Conventional and Alternative Myoelectric Control Strategy: A Study of Experienced and New Multiarticulating Hand Users.

Introduction: The development of multiarticulating hands holds the potential to restore lost function for upper-limb amputees. However, access to the full potential of commercialized devices is limited due to conventional control strategies for switching prosthesis modes, such as hand grips. For example, to switch grips in one conventional strategy, the prosthesis user must generate electromyogram (EMG) triggers (such as a cocontraction), which are cumbersome and nonintuitive.

Investigation of LKB1 Ser431 phosphorylation and Cys433 farnesylation using mouse knockin analysis reveals an unexpected role of prenylation in regulating AMPK activity.

The LKB1 tumour suppressor protein kinase functions to activate two isoforms of AMPK (AMP-activated protein kinase) and 12 members of the AMPK-related family of protein kinases. The highly conserved C-terminal residues of LKB1 are phosphorylated (Ser431) by PKA (cAMP-dependent protein kinase) and RSK (ribosomal S6 kinase) and farnesylated (Cys433) within a CAAX motif. To better define the role that these post-translational modifications play, we created homozygous LKB1S431A/S431A and LKB1C433S/C433S knockin mice.

Safety of cardiac magnetic resonance and contrast angiography for neonates and small infants: a 10-year single-institution experience.

Background: With increasing applications of cardiac magnetic resonance (CMR) and magnetic resonance angiography (MRA) for evaluation of congenital heart disease (CHD), safety of this technology in the very young is of particular interest.

Objective: We report our 10-year experience with CMR in neonates and small infants with particular focus on the safety profile and incidence of adverse events (AEs).

Materials And Methods: We reviewed clinical, anesthesia and nursing records of all children ≤120 days of age who underwent CMR.