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Direct electron detectors in scanning transmission electron microscopy give unprecedented possibilities for structure analysis at the nanoscale. In electronic and quantum materials, this new capability gives access to, for example, emergent chiral structures and symmetry-breaking distortions that underpin functional properties. Quantifying nanoscale structural features with statistical significance, however, is complicated by the subtleties of dynamic diffraction and coexisting contrast mechanisms, which often results in a low signal-to-noise ratio and the superposition of multiple signals that are challenging to deconvolute. Here we apply scanning electron diffraction to explore local polar distortions in the uniaxial ferroelectric Er(Mn,Ti)O3. Using a custom-designed convolutional autoencoder with bespoke regularization, we demonstrate that subtle variations in the scattering signatures of ferroelectric domains, domain walls, and vortex textures can readily be disentangled with statistical significance and separated from extrinsic contributions due to, e.g., variations in specimen thickness or bending. The work demonstrates a pathway to quantitatively measure symmetry-breaking distortions across large areas, mapping structural changes at interfaces and topological structures with nanoscale spatial resolution.

Abstract Covalent drug discovery efforts are growing rapidly but have major unaddressed limitations. These include high false positive rates during hit-to-lead identification; the inherent uncoupling of covalent drug concentration and effect [i.e., uncoupling of pharmacokinetics (PK) and pharmacodynamics (PD)]; and a lack of bioanalytical and modeling methods for determining PK and PD parameters. We present a covalent drug discovery workflow that addresses these limitations. Our bioanalytical methods are based upon a mass spectrometry (MS) assay that can measure the percentage of drug-target protein conjugation (% target engagement) in biological matrices. Further we develop an intact protein PK/PD model (iPK/PD) that outputs PK parameters (absorption and distribution) as well as PD parameters (mechanism of action, protein metabolic half-lives, dose, regimen, effect) based on time-dependent target engagement data. Notably, the iPK/PD model is applicable to any measurement (e.g., bottom-up MS and other drug binding studies) that yields % of target engaged. A Decision Tree is presented to guide researchers through the covalent drug development process. Our bioanalytical methods and the Decision Tree are applied to two approved drugs (ibrutinib and sotorasib); the most common plasma off-target, human serum albumin; three protein targets (KRAS, BTK, SOD1), and to a promising SOD1-targeting ALS drug candidates.

Proteoforms, which arise from post-translational modifications, genetic polymorphisms and RNA splice variants, play a pivotal role as drivers in biology. Understanding proteoforms is essential to unravel the intricacies of biological systems and bridge the gap between genotypes and phenotypes. By analysing whole proteins without digestion, top-down proteomics (TDP) provides a holistic view of the proteome and can decipher protein function, uncover disease mechanisms and advance precision medicine. This Primer explores TDP, including the underlying principles, recent advances and an outlook on the future. The experimental section discusses instrumentation, sample preparation, intact protein separation, tandem mass spectrometry techniques and data collection. The results section looks at how to decipher raw data, visualize intact protein spectra and unravel data analysis. Additionally, proteoform identification, characterization and quantification are summarized, alongside approaches for statistical analysis. Various applications are described, including the human proteoform project and biomedical, biopharmaceutical and clinical sciences. These are complemented by discussions on measurement reproducibility, limitations and a forward-looking perspective that outlines areas where the field can advance, including potential future applications.

Abstract Purpose This umbrella review aimed to summarise and synthesize the evidence on the outcomes reported and used to assess the value and or efficacy of geriatric assessments (GAs) for older adults with cancer. Methods Six electronic databases, PsycINFO, MEDLINE, Embase, CINAHL, Cochrane Library and Web of Science databases, were searched to identify systematic reviews with or without meta-analyses that described the value or outcomes of GAs for older adults with cancer. Results Twenty-six systematic reviews were included, of which six included a meta-analysis of the data. Thirteen associations and or outcomes were identified. Overall geriatric impairments predicted or were associated with majority of identified outcomes. However, the type of domains associated with outcomes differed within and across reviews. Only treatment toxicity was statistically significantly lower for patients allocated to the GA intervention group compared to standard care. Systematic reviews without meta-analyses demonstrated a positive impact of GA with management on treatment completion, communication and care planning and patient satisfaction with care. Conclusion There is evidence demonstrating the predictive value of GAs for older adults with cancer. GAs seems to be beneficial for older adults with cancer across some outcomes, with strong evidence demonstrating the impact of GA with management for treatment toxicity. However, there is mixed or limited evidence demonstrating the effect of GA in other treatment modalities, and on quality of life and economic outcomes.

Purpose: The purpose of this research was to investigate the relationship between horizontal jump distance, 10 m time, and 30–40 m time in multi-sport athletes separated by sex and sprint speed. Methods: A total of 1352 athletes (742 males and 610 females) performed 40 m sprints, standing broad jumps (SBJs), and standing triple jumps (STJs). Data were separated by sex and then grouped as fast, average, and slow using the K-Means algorithm in three conditions (acceleration, max speed, and combined). Results: Regression models explained 84.01% of the variance (F(7,757) = 574.5, p < 0.001) for the 10 m times with mass, speed group, and sex as significant predictors and 88.51% of the variance (F = (7,757 = 841.6, p < 0.001) for the 30–40 m times with SBJ, STJ, speed group, sex, and the interaction of sex and group as significant predictors. Conclusions: These results suggest that when examining general athlete physical performance, horizontal jump tests and max speed sprint times can be used equivalently to stratify athletes. However, it is important to group athletes by speed and sex before being able to predict sprint ability from horizontal jump tests. Further, athlete mass is a significant factor in the prediction of acceleration ability but not maximum speed, and horizontal jumps were significant factors in the prediction of max speed but not acceleration.

UNLABELLED: Patients with H3K27M-mutant diffuse midline glioma (DMG) have no proven effective therapies. ONC201 has recently demonstrated efficacy in these patients, but the mechanism behind this finding remains unknown. We assessed clinical outcomes, tumor sequencing, and tissue/cerebrospinal fluid (CSF) correlate samples from patients treated in two completed multisite clinical studies. Patients treated with ONC201 following initial radiation but prior to recurrence demonstrated a median overall survival of 21.7 months, whereas those treated after recurrence had a median overall survival of 9.3 months. Radiographic response was associated with increased expression of key tricarboxylic acid cycle-related genes in baseline tumor sequencing. ONC201 treatment increased 2-hydroxyglutarate levels in cultured H3K27M-DMG cells and patient CSF samples. This corresponded with increases in repressive H3K27me3 in vitro and in human tumors accompanied by epigenetic downregulation of cell cycle regulation and neuroglial differentiation genes. Overall, ONC201 demonstrates efficacy in H3K27M-DMG by disrupting integrated metabolic and epigenetic pathways and reversing pathognomonic H3K27me3 reduction. SIGNIFICANCE: The clinical, radiographic, and molecular analyses included in this study demonstrate the efficacy of ONC201 in H3K27M-mutant DMG and support ONC201 as the first monotherapy to improve outcomes in H3K27M-mutant DMG beyond radiation. Mechanistically, ONC201 disrupts integrated metabolic and epigenetic pathways and reverses pathognomonic H3K27me3 reduction. This article is featured in Selected Articles from This Issue, p. 2293.

PurposeVisual field testing is important for glaucoma diagnosis and management, but access to standard automated perimetry can be limited in some areas due to cost or access. Melbourne Rapid Fields-web (MRF-web) perimeter is designed to address these limitations by allowing perimetry testing on the flat screen of your personal computer.MethodsThis study is a retrospective, cross-sectional study involving two locations in Australia, one in metropolitan Melbourne and one in rural Dubbo NSW. 232 patients with stable glaucoma, glaucoma suspect or normal eyes were tested with MRF-web and outcomes were compared to the most recent Humphrey Field Analyzer (HFA) 24-2 SITA Faster test. Outcomes were compared by Deming regressions, Intraclass Correlation Coefficients (ICC) and Bland-Altman methods.ResultsPatient age ranged from 21 to 92 (average 66.3, SD 16.1). Bland-Altman found a bias of -0.50dB for Mean Deviation (MD) between the two tests, with 95% Limits of Agreement (LoA) of -6.80dB to 5.80dB. Pattern Deviation (PD) had a bias of -0.58dB with 95% LoA of -5.60dB to 4.40dB. High concordance was found for MD and PD, with ICCs of 0.87 and 0.73. No significant differences were found in false positive and fixation loss rates. Test time was approximately one minute longer for MRF-web compared to SITA-Faster. Area Under the Curve of MRF and HFA are similar indicating comparable diagnostic capacity.ConclusionMRF-web produces outcomes comparable to HFA SITA-Faster. Its portability and cost-effectiveness suggest suitability as an alternative method for visual field testing where a standard perimeter is not easily accessible.