Search

The SOX2 pioneer transcription factor performs critical roles in pluripotency and self-renewal of embryonic stem cells. Here the authors show that SOX2’s two nuclear localization signal sequences form a contiguous binding interface on the nuclear import receptor importin-α3, and provide a structural basis for the preference of SOX2 binding to IMPα3.

Sustainable and innovative programs to support students in their transition to university and improve student progress rates and retention are in high demand and short supply. An institution-wide model was established for an online Embedded Tutor Program. The program supports commencing undergraduate students and is sustainable post-pandemic. Tutors with unit-specific knowledge were embedded in 98 first-year unit offerings across the university in 2022. Tutors met with students via Zoom to provide feedforward on a written assessment. Of the 1080 students who met with a tutor, assessment marks were on average 8% higher and cumulative unit marks were 15% higher, and the one-on-one tutor support improved students' perceived confidence, overall learning and satisfaction. The Embedded Tutor Program had positive outcomes for all participants; however, students with multiple equity factors benefited the most from the support.

Universities actively promote themselves to potential students, control admissions and deliver programs of study. For most students globally, there are financial costs to attending university. At the extreme end of failure are students who receive 'zero-fails': they enrol, do not submit any assessments, and receive a mark of 0 out of 100. A quantitative descriptive analysis was performed and provides student performance details for bachelor-level students enrolled in a large, regional Australian university from 2019-2021. At a unit level, zero-fails accounted for 20% of all failing grades. There was a significant increase in zero-fail grades in 2020 and 2021 compared to 2019. However, zero-fails are not entirely a COVID-19 phenomenon. Only 8% of students who received any zero-fail grade in their commencing semester of study continued onto their second semester and passed most of their units. We argue universities operating in countries with deferred payment schemes such as Australia and the United Kingdom have a responsibility to track unit failure in finer detail and consider ways to mitigate debt associated with students who are clearly not receiving value from their educational experience. This must be done as we continue to expand higher education opportunities to students from non-traditional backgrounds.

Dengue virus (DENV) threatens almost 70% of the world’s population, with no effective vaccine or therapeutic currently available. A key contributor to infection is nuclear localisation in the infected cell of DENV nonstructural protein 5 (NS5) through the action of the host importin (IMP) α/β1 proteins. Here, we used a range of microscopic, virological and biochemical/biophysical approaches to show for the first time that the small molecule GW5074 has anti-DENV action through its novel ability to inhibit NS5–IMPα/β1 interaction in vitro as well as NS5 nuclear localisation in infected cells. Strikingly, GW5074 not only inhibits IMPα binding to IMPβ1, but can dissociate preformed IMPα/β1 heterodimer, through targeting the IMPα armadillo (ARM) repeat domain to impact IMPα thermal stability and α-helicity, as shown using analytical ultracentrifugation, thermostability analysis and circular dichroism measurements. Importantly, GW5074 has strong antiviral activity at low µM concentrations against not only DENV-2, but also zika virus and West Nile virus. This work highlights DENV NS5 nuclear targeting as a viable target for anti-flaviviral therapeutics.

The Gcn5-related N-acetyltransferases (GNATs) are ubiquitously expressed in nature and perform a diverse range of cellular functions through the acetylation of small molecules and protein substrates. Using activated acetyl coenzyme A as a common acetyl donor, GNATs catalyse the transfer of an acetyl group to acceptor molecules including aminoglycoside antibiotics, glucosamine-6-phosphate, histones, serotonin and spermidine. There is often only very limited sequence conservation between members of the GNAT superfamily, in part, reflecting their capacity to bind a diverse array of substrates. In contrast, the secondary and tertiary structures are highly conserved, but then at the quaternary level there is further diversity, with GNATs shown to exist in monomeric, dimeric, or tetrameric states. Here we describe the X-ray crystallographic structure of a GNAT enzyme from Staphylococcus aureus with only low sequence identity to previously solved GNAT proteins. It contains many of the classical GNAT motifs, but lacks other hallmarks of the GNAT fold including the classic β-bulge splayed at the β-sheet interface. The protein is likely to be a dimer in solution based on analysis of the asymmetric unit within the crystal structure, homology with related GNAT family members, and size exclusion chromatography. The study provides the first high resolution structure of this enzyme, providing a strong platform for substrate and cofactor modelling, and structural/functional comparisons within this diverse enzyme superfamily.

The translocation of macromolecules into the nucleus is a fundamental eukaryotic process, regulating gene expression, cell division and differentiation, but which is impaired in a range of significant diseases including cancer and viral infection. The import of proteins into the nucleus is generally initiated by a specific, high affinity interaction between nuclear localisation signals (NLSs) and nuclear import receptors in the cytoplasm, and terminated through the disassembly of these complexes in the nucleus. For classical NLSs (cNLSs), this import is mediated by the importin-α (IMPα) adaptor protein, which in turn binds to IMPβ to mediate translocation of nuclear cargo across the nuclear envelope. The interaction and disassembly of import receptor:cargo complexes is reliant on the differential localisation of nucleotide bound Ran across the envelope, maintained in its low affinity, GDP-bound form in the cytoplasm, and its high affinity, GTP-bound form in the nucleus. This in turn is maintained by the differential localisation of Ran regulating proteins, with RanGAP in the cytoplasm maintaining Ran in its GDP-bound form, and RanGEF (Prp20 in yeast) in the nucleus maintaining Ran in its GTP-bound form. Here, we describe the 2.1 Å resolution x-ray crystal structure of IMPα in complex with the NLS of Prp20. We observe 1,091 Å(2) of buried surface area mediated by an extensive array of contacts involving residues on armadillo repeats 2-7, utilising both the major and minor NLS binding sites of IMPα to contact bipartite NLS clusters (17)RAKKMSK(23) and (3)KR(4), respectively. One notable feature of the major site is the insertion of Prp20NLS Ala(18) between the P0 and P1 NLS sites, noted in only a few classical bipartite NLSs. This study provides a detailed account of the binding mechanism enabling Prp20 interaction with the nuclear import receptor, and additional new information for the interaction between IMPα and cargo.

There is a small window of opportunity at the beginning of semester for a university to provide commencing students with timely and targeted support. However, there is limited information available on interventions that identify and support disengaged students from equity groups without using equity group status as the basis for the contact. The aim of this study was to use learning analytics that were explainable to the end users to identify and support commencing undergraduate students at an Australian regional university. Non-submission of an early assessment item accurately identified disengaged students and those students with successful dialogue with the Outreach Team were less likely to receive a failing grade. Analysis of intersectionality revealed that student progress rate decreased with additional equity factors. A holistic conversation with the Outreach Team increased retention for equity students the following semester, indicating that explainable learning analytics can be used to support equity students.