Objectives/Goals: The never in mitosis kinase (NEK) family regulates vital processes, namely cell cycle progression, but their potential as therapeutic targets in TNBC has not been fully explored. Our studies aim to develop a toolkit to investigate the functional roles of NEKs in pathologies including carcinogenesis. Methods/Study Population: To assess differential NEK expression in normal and tumor tissues and correlation of gene expression with patient survival, we used Gene Expression Profiling Interactive Analysis (GEPIA) and Kaplan–Meier Plotter (KMPlot) pan-cancer analysis, respectively. Basal NEK protein levels were determined by immunoblot across a panel of cell lines, including breast cancer, osteosarcoma, hepatocellular carcinoma, and non-cancerous cells, to identify appropriate systems for evaluation of NEK function. Doxycycline-inducible cell lines were generated by transduction with lentiviral stocks of NEK shRNA and overexpression constructs and antibiotic selection. Expression was analyzed by qPCR and immunoblot. Results/Anticipated Results: Expression of NEK2, 4, 5, 6, 8, and 11 was higher in breast tumors compared to normal tissue by GEPIA analysis. Further examination using KMPlot showed a correlation between elevated NEK6 expression and decreased overall survival in patients with aggressive cancers. As an initial proof-of-concept study, we analyzed NEK6 protein expression in breast cancer cells. Levels of NEK6 were elevated in TNBC cells (MDA-MB-231) compared to hormone receptor positive (HR+) breast cancer cells (MCF7). Using complementary approaches to investigate the functional role of NEK6 in breast cancer, we depleted NEK6 expression using shRNAs in TNBC cells and expressed NEK6 in HR+ cells Discussion/Significance of Impact: Because kinase dysregulation promotes oncogenesis and metastasis, targeting kinases is a key strategy in therapeutic development. A NEK-specific molecular toolkit allows researchers to elucidate NEK functions and contributions to carcinogenesis, promoting advancement of novel therapies.

Vaccines have revolutionised the field of medicine, eradicating and controlling many diseases. Recent pandemic vaccine successes have highlighted the accelerated pace of vaccine development and deployment. Leveraging this momentum, attention has shifted to cancer vaccines and personalised cancer vaccines, aimed at targeting individual tumour-specific abnormalities. The UK, now regarded for its vaccine capabilities, is an ideal nation for pioneering cancer vaccine trials. This article convened experts to share insights and approaches to navigate the challenges of cancer vaccine development with personalised or precision cancer vaccines, as well as fixed vaccines. Emphasising partnership and proactive strategies, this article outlines the ambition to harness national and local system capabilities in the UK; to work in collaboration with potential pharmaceutic partners; and to seize the opportunity to deliver the pace for rapid advances in cancer vaccine technology.

Since 1974, two out of every five constitutions (40.3%) were prepared via processes that included public consultation. The reasons for adopting these participatory mechanisms, however, are largely unexplored. I argue that public consultation is a tool for elite contestation of power. Introducing an original dataset of public consultations in constitution-making processes from 1974–2021 (n = 300), I find that in democracies, factional majorities and newcomer elites use public consultation to legitimate a break from the status quo. In autocracies, governing coalitions that depend on performance and enjoy greater party institutionalization push for public consultation to preserve favorable power-sharing arrangements.

Group A streptococcal or Streptococcus pyogenes infections have been increasing post-COVID-19 pandemic. We describe the epidemiology of S. pyogenes pharyngitis and invasive disease in Alberta, Canada 2018–2023. Positive pharyngitis specimens were identified from throat swabs collected from pharyngitis patients. Invasive S. pyogenes was defined as the isolation of S. pyogenes from a normally sterile site or severe skin infection. S. pyogenes isolates were emm typed. Pharyngitis and invasive disease displayed seasonal trends preceding the COVID-19 pandemic followed by a sharp decrease during COVID-19 intervention measures. After the lifting of interventions, rates of pharyngitis and invasive disease rose. There were 182 983 positive pharyngitis specimens between 2018 and 2023 for a positivity rate of 17.6%. The highest rates occurred in the 0–9 age group in 2023 (41.5%). Invasive disease increased in 2022–2023 driven by emm1 and 12 types. M1UK strain was the most frequent M1 type associated with invasive disease (59% of M1 isolates sequenced). Notably, out of 182 983 pharyngitis cases, there were 111 cases of invasive S. pyogenes detected for an invasive disease rate of 0.06%. This descriptive epidemiology of S. pyogenes pharyngitis and invasive S. pyogenes disease highlights the rapid increase in cases of S. pyogenes occurring in western Canada and illustrates the critical need for a vaccine.

Recent reports suggest the ON and OFF pathways are differentially susceptible to selective vision loss in glaucoma. Thus, perimetric assessment of ON- and OFF-pathway function may serve as a useful diagnostic. However, this necessitates a developed understanding of normal ON/OFF pathway function around the visual field and as a function of input intensity. Here, using electroencephalography, we measured ON- and OFF-pathway biased contrast response functions in the upper and lower visual fields. Using the steady-state visually evoked potential paradigm, we flickered achromatic luminance probes according to a saw-tooth waveform, the fast phase of which biased responses towards the ON or OFF pathways. Neural responses from the upper and lower visual fields were simultaneously measured using frequency tagging - probes in the upper visual field modulated at 3.75 Hz, while those in the lower visual field modulated at 3 Hz. We find that responses to OFF/decrements are larger than ON/increments, especially in the lower visual field. In the lower visual field, both ON and OFF responses were well described by a sigmoidal non-linearity. In the upper visual field, the ON pathway function was very similar to that of the lower, but the OFF pathway function showed reduced saturation and more cross-subject variability. Overall, this demonstrates that the relationship between the ON and OFF pathways depends on the visual field location and contrast level, potentially reflective of natural scene statistics.