Cancer cells exploit a mesenchymal-like transcriptional state (MLS) to survive drug treatments. Although the MLS is well characterized, few therapeutic vulnerabilities targeting this program have been identified. Here, we systematically identify the dependency network of mesenchymal-like cancers through an analysis of gene essentiality scores in ~800 cancer cell lines, nominating a poorly studied kinase, PKN2, as a top therapeutic target of the MLS. Co-essentiality relationships, biochemical experiments, and genomic analyses of patient tumors revealed that PKN2 promotes mesenchymal-like cancer growth through a PKN2-SAV1-TAZ signaling mechanism. Notably, pairing genetic PKN2 inhibition with clinically relevant targeted therapies against EGFR, KRAS, and BRAF oncogenes suppresses drug resistance by depleting mesenchymal-like drug-tolerant persister cells. These findings provide evidence that PKN2 is a core regulator of the Hippo tumor suppressor pathway and highlight the potential of PKN2 inhibition as a generalizable therapeutic strategy to overcome drug resistance driven by the MLS across cancer contexts.

Mossy cells (MCs) in the hilus of the dentate gyrus (DG) are important for regulating activity of dentate granule cells and are particularly vulnerable to excitotoxic damage in epilepsy. Recent studies have demonstrated that MCs in the dorsal and ventral DG differ in the patterns of their axonal projections and neurochemical identities. Such differences raised questions about the vulnerability and plasticity of dorsal and ventral MCs in epilepsy and led to this study using a mouse pilocarpine model of epilepsy. Dorsal MCs were labeled by transfection of Cre-dependent eYFP in the dorsal DG of mice that express Cre selectively in MCs. Ventral MCs were labeled with calretinin (CR), which labels ventral but not dorsal MCs. At 6-8 weeks after pilocarpine treatment, MC loss and axonal projections of remaining MCs were studied in control and pilocarpine-treated mice with confocal microscopy. Dorsal MCs were severely depleted, but many ventral MCs remained, and quantitative analysis of GluA2-labeled hilar neurons demonstrated a proportionally greater loss of dorsal MCs (77.6% loss) than ventral MCs (21.5% loss). Loss of dorsal MCs led to a marked reduction in the dorsal commissural pathway, while the remaining ventral MCs maintained a prominent, though reduced, ventral to dorsal association pathway. In pilocarpine-treated animals, a plexus of CR-labeled fibers extended into the middle molecular layer, suggesting axonal sprouting of remaining ventral MCs, with some of these fibers in contact with parvalbumin-labeled dendrites. These findings suggest that dorsal and ventral MCs differ in their vulnerability to seizure-induced damage in this animal model, creating an imbalance between the dorsal and ventral MC pathways that could alter the excitatory/inhibitory balance within the dentate gyrus.

To analyse patterns of glucose-lowering therapies among people with type 2 diabetes (T2D) in Denmark from 2016 to 2023.

Platinum particle growth during long-term operations is one of the well-known bottlenecks offsetting the performance and stability of Pt-based electrocatalysts in polymer electrolyte membrane (PEM) fuel cells and PEM water electrolyzers. In this research, the addition of certain ceramic nanoparticulate additives to the catalyst ink was evaluated as a means of improving the electrochemical stability of a carbon-supported platinum (Pt/C) electrocatalyst in gas diffusion electrodes (GDEs) during an accelerated stress test (AST). GDEs prepared using three nanoparticulate ceramic additives (TiN, ATO, and TiO) with three loadings (replacing 5, 10, and 15 wt % of the catalyst) were studied for their electrochemical performance, i.e., the initial electrochemical surface area (ECSA) and stability during AST in a liquid cell. TiN appeared to be an optimal additive among the three to (i) improve the stability by ∼40% during 1600 cycles, (ii) prohibit Pt nanoparticle agglomeration due to coalescence and Ostwald ripening, and (iii) reduce Pt dissolution during the AST, without compromising a high initial ECSA. The fundamental mechanism lies in the fact that the ceramic nanoparticles can act as additional nucleation sites for redeposition of the dissolved Pt during AST; X-ray photoelectron spectroscopy (XPS) indicates strong interactions between platinum and ceramic nanoparticles. Eventually, the superior sample was used as the cathode catalyst in an electrolyzer to compare the electrochemical performance with that of a commercial Pt/C sample. As confirmed by single-cell tests in this research, the method studied and the associated concept here to enhance the durability of Pt-based electrocatalysts are facile and scalable and hence may be readily adopted by relevant stakeholders.

To compare prostate monoparametric MRI (monoMRI), which uses only diffusion-weighted imaging (DWI), with biparametric (bpMRI) and multiparametric MRI (mpMRI) in detecting clinically significant cancer (CSC) and to evaluate the effect of the combination of monoMRI results and prostate-specific antigen (PSA) level.

Early embryogenesis is driven by transcription factors (TFs) that first activate the zygotic genome and then specify the lineages constituting the blastocyst. Although the TFs specifying the blastocyst's lineages are well characterized, those playing earlier roles remain poorly defined. Using mouse models of the TF , we show that embryos arrest at the early morula stage and exhibit altered lineage specification, frequent mitotic failure, and substantial chromosome segregation defects. Although NR5A2 plays a minor but measurable role during zygotic genome activation, it predominantly acts as a master regulator at the eight-cell stage, controlling expression of lineage-specifying TFs and genes involved in mitosis, telomere maintenance, and DNA repair. We conclude that NR5A2 coordinates proliferation, genome stability, and lineage specification to ensure correct morula development.

The detection of numerous and relatively bright galaxies at redshifts > 9 has prompted new investigations into the star-forming properties of high-redshift galaxies. Using local forms of the initial mass function (IMF) to estimate stellar masses of these galaxies from their light output leads to galaxy masses that are at the limit allowed for the state of the Lambda Cold Dark Matter (ΛCDM) Universe at their redshift. We explore how varying the IMF assumed in studies of galaxies in the early universe changes the inferred values for the stellar masses of these galaxies. We infer galaxy properties with the spectral energy distribution (SED) fitting code Prospector using varying IMF parameterizations for a sample of 102 galaxies with photometry from the James Webb Space Telescope, JWST Advanced Deep Extragalactic Survey that are spectroscopically confirmed to be at [Formula: see text], with additional photometry from the JWST Extragalactic Medium Band Survey for twenty-one of the galaxies. We demonstrate that models with stellar masses reduced by a factor of three or more do not affect the modeled SED.

Provision of non-invasive vascular imaging results to individuals has been shown to improve cardiovascular disease risk factor control: its impact on diet remains uncertain. In this two-arm, single-blind, parallel, 12-week randomized controlled trial, 240 participants, 57.5% females aged 60-80 y had abdominal aortic calcification and clinical assessments performed at a hospital clinic. Participants were randomized 1:1 to receive (intervention n = 121) or not (control n = 119) their calcification results. Both groups received educational resources on cardiovascular disease risk control and were unblinded to the intervention. Outcome measures were performed at baseline and 12 weeks. The primary outcomes of the study were changes in fruit and vegetable intake measures over 12 weeks assessed using plasma carotenoid concentrations (biomarkers of FV intake) and a food frequency questionnaire. Secondary outcomes included 12-week changes in other aspects of the diet, physical activity, body weight, blood pressure, heart rate, lipid profile, glucose concentrations, estimated cardiovascular disease risk score, and medication use. Between-group differences were tested using linear mixed-effects regression. There were no between-group differences in the primary outcomes at 12 weeks: plasma carotenoids (mean difference +0.03 µg/mL [95%CI -0.06, 0.13]) and fruit and vegetable intakes (+18 g/d [-37, 72]). However, the provision of calcification results led to between-group differences in serum total (-0.22 mmol/L [-0.41, -0.04]) and non-HDL (-0.19 mmol/L [-0.35, -0.03]) cholesterol, and estimated cardiovascular disease risk score (-0.24% [-0.47, -0.02]). No between-group differences were seen for other secondary outcomes. In this work, providing vascular imaging results did not improve diet but did improve some cardiovascular disease risk factors (Australian and New Zealand Clinical Trials Registry ACTRN12618001087246).

The implementation of microsampling approaches for use in nonclinical discovery and development pharmaceutical studies can have a major impact on improving animal ethics through the use of fewer animals and less invasive procedures for the collection of toxicokinetic and pharmacokinetic samples. In addition, the approach offers the opportunity for obtaining improved quality of data for these studies. This can include the determination of additional timepoints and endpoints, and the ability to obtain exposure data from the same animals utilized to measure other study endpoints. This manuscript presents a number of cases where a variety of microsampling approaches have been successfully implemented by a number of organizations and serves as a guide for those considering the use of microsampling approaches as part of their drug discovery and development programs, as the adoption of these approaches are not yet universal.

Rhodamines have been continuously optimized in brightness, biocompatibility, and color to fulfill the demands of modern bioimaging. However, the problem of phototoxicity caused by the excited fluorophore under long-term illumination has been largely neglected, hampering their use in time-lapse imaging. Here we introduce cyclooctatetraene (COT) conjugated rhodamines that span the visible spectrum and exhibit significantly reduced phototoxicity. We identified a general strategy for the generation of Gentle Rhodamines, which preserved their outstanding spectroscopic properties and cell permeability while showing an efficient reduction of singlet-oxygen formation and diminished cellular photodamage. Paradoxically, their photobleaching kinetics do not go hand in hand with reduced phototoxicity. By combining COT-conjugated spirocyclization motifs with targeting moieties, these Gentle Rhodamines compose a toolkit for time-lapse imaging of mitochondria, DNA, and actin, and synergize with covalent and exchangeable HaloTag labeling of cellular proteins with less photodamage than their commonly used precursors. Taken together, the Gentle Rhodamines generally offer alleviated phototoxicity and allow advanced video recording applications, including voltage imaging.

Enhancing iridium (Ir)-based electrocatalysts to achieve high activity and robust durability for the oxygen evolution reaction (OER) in acidic environments has been an ongoing mission in the commercialization of proton exchange membrane (PEM) electrolyzers. In this study, we present the synthesis of carbon-supported Ir nanoparticles (NPs) using a modified impregnation method followed by solid-state reduction, with Ir loadings of 20 and 40 wt % on carbon. Among the catalysts, the sample with an Ir loading of 20 wt % synthesized at 1000 °C with a heating rate of 300 °C/h demonstrated the highest mass-normalized OER performance of 1209 A g and an OER current retention of 80% after 1000 cycles of cyclic voltammetry (CV). High-resolution STEM images confirmed the uniform dispersion of NPs, with diameters of 1.6 ± 0.4 nm across the support. XPS analysis revealed that the C-O and C═O peaks shifted slightly toward higher binding energies for the best-performing catalyst. In comparison, the metallic Ir state shifted toward lower binding energies compared to other samples. This suggests electron transfer from the carbon support to the Ir NPs, indicating a potential interaction between the catalyst and the support. This work underscores the strong potential of the solid-state method for the scalable synthesis of supported Ir catalysts.

Poly(ethylene oxide) (PEO)-based solid polymer electrolytes (SPEs) are among the most promising materials for solid-state lithium metal batteries (LMBs) due to their inherent safety advantages; however, they suffer from insufficient room-temperature ionic conductivity (up to 10 S cm) and limited oxidation stability (<4 V). In this study, a novel "polymer-in-high-concentrated ionic liquid (IL)" (PiHCIL) electrolyte composed of PEO, -propyl--methylpyrrolidinium bis(fluorosulfonyl) imide (CmpyrFSI) IL, and LiFSI is designed. The EO/[Li/IL] ratio has been widely varied, and physical and electrochemical properties have been explored. The Li-coordination and solvation structure has been explored through Fourier-transform infrared spectroscopy and solid-state magic-angle spinning nuclear magnetic resonance. The newly designed electrolyte provides a promisingly high oxidative stability of 5.1 V and offers high ambient temperature ionic conductivity of 5.6 × 10 S cm at 30 °C. Li|Li symmetric cell cycling shows very stable and reversible cycling of Li metal over 100 cycles and a smooth dendrite-free deposition morphology. All-solid-state cells using a composite lithium iron phosphate cathode exhibit promising cycling with 99.2% capacity retention at a C/5 rate over 100 cycles. Therefore, the novel approach of PiHCIL enables a new pathway to design high-performing SPEs for high-energy-density all-solid-state LMBs.

Pre-clinical studies suggest that extracts prepared from the fruits of (VAC) interact with dopamine D2 receptors, leading to reduced prolactin secretion. In previous experiments, dopaminergic activity was mostly evaluated using radioligand binding assays or via the inhibition of prolactin release from rat pituitary cells. Diterpenes featuring a clerodadienol scaffold were identified as major active compounds, but no conclusive data regarding their potency and intrinsic activity are available. Utilising advances in chromatography, we re-examined this topic using HPLC-based tracking of bioactivity via microfractionation of the VAC extract Ze 440. Using a cAMP-based assay, we measured dopaminergic activity in CHO-K1 cells that overexpress the human D2 receptor. Six diterpenes were isolated from two active HPLC microfractions. Viteagnusin I emerged as the most potent diterpene (EC: 6.6 µM), followed by rotundifuran (EC: 12.8 µM), whereas vitexilactone was inactive (EC: >50 µM). Interestingly, triterpenes were also identified as active, with 3--maslinic acid being the most active compound (EC: 5.1 µM). To better understand these interactions at the molecular level, selected diterpenes and triterpenes were analysed through molecular docking against D2 receptor structures. Our data show that the dopaminergic activity of VAC diterpenes seems to depend on the configuration and on ring substitution in the side chain. This study also highlights for the first time the dopaminergic contribution of triterpenes such as 3-epi-maslinic acid.

Purpose To determine whether the unsupervised domain adaptation (UDA) method with generated images improves the performance of a supervised learning (SL) model for prostate cancer (PCa) detection using multisite biparametric (bp) MRI datasets. Materials and Methods This retrospective study included data from 5150 patients (14 191 samples) collected across nine different imaging centers. A novel UDA method using a unified generative model was developed for PCa detection using multisite bpMRI datasets. This method translates diffusion-weighted imaging (DWI) acquisitions, including apparent diffusion coefficient (ADC) and individual diffusion-weighted (DW) images acquired using various values, to align with the style of images acquired using values recommended by Prostate Imaging Reporting and Data System (PI-RADS) guidelines. The generated ADC and DW images replace the original images for PCa detection. An independent set of 1692 test cases (2393 samples) was used for evaluation. The area under the receiver operating characteristic curve (AUC) was used as the primary metric, and statistical analysis was performed via bootstrapping. Results For all test cases, the AUC values for baseline SL and UDA methods were 0.73 and 0.79 ( < .001), respectively, for PCa lesions with PI-RADS score of 3 or greater and 0.77 and 0.80 ( < .001) for lesions with PI-RADS scores of 4 or greater. In the 361 test cases under the most unfavorable image acquisition setting, the AUC values for baseline SL and UDA were 0.49 and 0.76 ( < .001) for lesions with PI-RADS scores of 3 or greater and 0.50 and 0.77 ( < .001) for lesions with PI-RADS scores of 4 or greater. Conclusion UDA with generated images improved the performance of SL methods in PCa lesion detection across multisite datasets with various values, especially for images acquired with significant deviations from the PI-RADS-recommended DWI protocol (eg, with an extremely high value). Prostate Cancer Detection, Multisite, Unsupervised Domain Adaptation, Diffusion-weighted Imaging, Value © RSNA, 2024.

To assess incidence rates of clinically diagnosed eating disorders among Danish youth before, during, and after the COVID-19 pandemic.

Reverse epidemiology is a mathematical modelling tool used to ascertain information about the source of a pathogen, given the spatial and temporal distribution of cases, hospitalisations and deaths. In the context of a deliberately released pathogen, such as Bacillus anthracis (the disease-causing organism of anthrax), this can allow responders to quickly identify the location and timing of the release, as well as other factors such as the strength of the release, and the realized wind speed and direction at release. These estimates can then be used to parameterise a predictive mechanistic model, allowing for estimation of the potential scale of the release, and to optimise the distribution of prophylaxis. In this paper we present two novel approaches to reverse epidemiology, and demonstrate their utility in responding to a simulated deliberate release of B. anthracis in ten locations in the UK and compare these to the standard grid-search approach. The two methods-a modified MCMC and a Recurrent Convolutional Neural Network-are able to identify the source location and timing of the release with significantly better accuracy compared to the grid-search approach. Further, the neural network method is able to do inference on new data significantly quicker than either the grid-search or novel MCMC methods, allowing for rapid deployment in time-sensitive outbreaks.

Unilateral subthalamic nucleus (STN) ablation using magnetic resonance-guided focused ultrasound (MRgFUS) is being explored as a new treatment for asymmetric Parkinson's disease (PD).

Lung cancer is one of the most common types of cancer in the United Kingdom. It is often diagnosed late. The 5-year survival rate for lung cancer is below 10%. Early diagnosis may improve survival. Software that has an artificial intelligence-developed algorithm might be useful in assisting with the identification of suspected lung cancer.

This study aims to assess cost-effectiveness of caudal epidural block with transforaminal nerve root block in the treatment of degenerative diseases of the lumbar spine.

This study aims to describe a kinematic gait assessment protocol and identify its main alterations in individuals with cervical spondylotic myelopathy (CSM) compared to healthy patients.