This Special Report presents a description of Geant4‐DNA user applications dedicated to the simulation of track structures (TS) in liquid water and associated physical quantities (e.g., range, ...stopping power, mean free path…). These example applications are included in the Geant4 Monte Carlo toolkit and are available in open access. Each application is described and comparisons to recent international recommendations are shown (e.g., ICRU, MIRD), when available. The influence of physics models available in Geant4‐DNA for the simulation of electron interactions in liquid water is discussed. Thanks to these applications, the authors show that the most recent sets of physics models available in Geant4‐DNA (the so‐called “option4” and “option 6” sets) enable more accurate simulation of stopping powers, dose point kernels, and W‐values in liquid water, than the default set of models (“option 2”) initially provided in Geant4‐DNA. They also serve as reference applications for Geant4‐DNA users interested in TS simulations.
Peripheral artery disease (PAD) is a common cardiovascular disorder that is frequently underdiagnosed, which can lead to poorer outcomes due to lower rates of medical optimization. We aimed to ...develop an automated tool to identify undiagnosed PAD and evaluate physician acceptance of a dashboard representation of risk assessment. Data were derived from electronic health records (EHR). We developed and compared traditional risk score models to novel machine learning models. For usability testing, primary and specialty care physicians were recruited and interviewed until thematic saturation. Data from 3168 patients with PAD and 16,863 controls were utilized. Results showed a deep learning model that utilized time engineered features outperformed random forest and traditional logistic regression models (average AUCs 0.96, 0.91 and 0.81, respectively), P < 0.0001. Of interviewed physicians, 75% were receptive to an EHR-based automated PAD model. Feedback emphasized workflow optimization, including integrating risk assessments directly into the EHR, using dashboard designs that minimize clicks, and providing risk assessments for clinically complex patients. In conclusion, we demonstrate that EHR-based machine learning models can accurately detect risk of PAD and that physicians are receptive to automated risk detection for PAD. Future research aims to prospectively validate model performance and impact on patient outcomes.
Disease-modifying osteoarthritis drugs (DMOADs) should reach their intra-tissue target sites at optimal doses for clinical efficacy. The dense, negatively charged matrix of cartilage poses a major ...hindrance to the transport of potential therapeutics. In this work, electrostatic interactions were utilised to overcome this challenge and enable higher uptake, full-thickness penetration and enhanced retention of dexamethasone (Dex) inside rabbit cartilage. This was accomplished by using the positively charged glycoprotein avidin as nanocarrier, conjugated to Dex by releasable linkers. Therapeutic effects of a single intra-articular injection of low dose avidin-Dex (0.5 mg Dex) were evaluated in rabbits 3 weeks after anterior cruciate ligament transection (ACLT). Immunostaining confirmed that avidin penetrated the full cartilage thickness and was retained for at least 3 weeks. Avidin-Dex suppressed injury-induced joint swelling and catabolic gene expression to a greater extent than free Dex. It also significantly improved the histological score of cell infiltration and morphogenesis within the periarticular synovium. Micro-computed tomography confirmed the reduced incidence and volume of osteophytes following avidin-Dex treatment. However, neither treatment restored the loss of cartilage stiffness following ACLT, suggesting the need for a combinational therapy with a pro-anabolic factor for enhancing matrix biosynthesis. The avidin dose used caused significant glycosaminoglycan (GAG) loss, suggesting the use of higher Dex : avidin ratios in future formulations, such that the delivered avidin dose could be much less than that shown to affect GAGs. This charge-based delivery system converted cartilage into a drug depot that could also be employed for delivery to nearby synovium, menisci and ligaments, enabling clinical translation of a variety of DMOADs.
We report on the first proton-induced single proton- and neutron-removal reactions from the neutron-deficient ^{14}O nucleus with large Fermi-surface asymmetry S_{n}-S_{p}=18.6 MeV at ∼100 ...MeV/nucleon, a widely used energy regime for rare-isotope studies. The measured inclusive cross sections and parallel momentum distributions of the ^{13}N and ^{13}O residues are compared to the state-of-the-art reaction models, with nuclear structure inputs from many-body shell-model calculations. Our results provide the first quantitative contributions of multiple reaction mechanisms including the quasifree knockout, inelastic scattering, and nucleon transfer processes. It is shown that the inelastic scattering and nucleon transfer, usually neglected at such energy regime, contribute about 50% and 30% to the loosely bound proton and deeply bound neutron removal, respectively. These multiple reaction mechanisms should be considered in analyses of inclusive one-nucleon removal cross sections measured at intermediate energies for quantitative investigation of single-particle strengths and correlations in atomic nuclei.
The Gene Ontology (GO) is a comprehensive resource of computable knowledge regarding the functions of genes and gene products. As such, it is extensively used by the biomedical research community for ...the analysis of -omics and related data. Our continued focus is on improving the quality and utility of the GO resources, and we welcome and encourage input from researchers in all areas of biology. In this update, we summarize the current contents of the GO knowledgebase, and present several new features and improvements that have been made to the ontology, the annotations and the tools. Among the highlights are 1) developments that facilitate access to, and application of, the GO knowledgebase, and 2) extensions to the resource as well as increasing support for descriptions of causal models of biological systems and network biology. To learn more, visit http://geneontology.org/.
Highlights • A review of the current status of Geant4-DNA is presented. • New physical models describing the interactions of electrons in water are described. • Physicochemical and chemical stages of ...water radiolysis can be simulated. • Several approaches are available for modeling geometries of biological targets. • Dedicated examples are proposed to demonstrate such capabilities.
•5 patients with pelvic lymph node metastases received SBRT using a 1.5 T MR-linac.•Session time was <60 min for all 25 treatment fractions.•All quality assurance tests were passed (dose calculations ...& film measurements).
Online adaptive radiotherapy using the 1.5 Tesla MR-linac is feasible for SBRT (5 × 7 Gy) of pelvic lymph node oligometastases. The workflow allows full online planning based on daily anatomy. Session duration is less than 60 min. Quality assurance tests, including independent 3D dose calculations and film measurements were passed.
The extracellular matrix (ECM) and its receptors make diverse contributions to development. The ECM comes in a variety of forms, including the more "standard" ECM that is internal to the animal and ...on the basal side of epithelial sheets, as well as the apical ECM, which is especially elaborated in the invertebrates to form the exoskeleton. ECM proteins accumulate adjacent to particular target tissues in the developing animal by a variety of mechanisms: local synthesis in the target tissue; local synthesis by migrating cells; and secretion from a distant source and capture by the target tissue. The diverse developmental functions of the ECM are discussed, including the generation of a road for cell migration, creation of morphogenetic checkpoints for differentiation, modulation of morphogen gradients, insulation of organs, gluing together cell layers, and providing structure for the organism.
Using a Drosophila model of Alzheimer's disease (AD), we systematically evaluated 67 candidate genes based on AD-associated genomic loci (P < 10(-4)) from published human genome-wide association ...studies (GWAS). Genetic manipulation of 87 homologous fly genes was tested for modulation of neurotoxicity caused by human Tau, which forms neurofibrillary tangle pathology in AD. RNA interference (RNAi) targeting 9 genes enhanced Tau neurotoxicity, and in most cases reciprocal activation of gene expression suppressed Tau toxicity. Our screen implicates cindr, the fly ortholog of the human CD2AP AD susceptibility gene, as a modulator of Tau-mediated disease mechanisms. Importantly, we also identify the fly orthologs of FERMT2 and CELF1 as Tau modifiers, and these loci have been independently validated as AD susceptibility loci in the latest GWAS meta-analysis. Both CD2AP and FERMT2 have been previously implicated with roles in cell adhesion, and our screen additionally identifies a fly homolog of the human integrin adhesion receptors, ITGAM and ITGA9, as a modifier of Tau neurotoxicity. Our results highlight cell adhesion pathways as important in Tau toxicity and AD susceptibility and demonstrate the power of model organism genetic screens for the functional follow-up of human GWAS.
The Gene Ontology (GO; http://www.geneontology.org) is a community-based bioinformatics resource that supplies information about gene product function using ontologies to represent biological ...knowledge. Here we describe improvements and expansions to several branches of the ontology, as well as updates that have allowed us to more efficiently disseminate the GO and capture feedback from the research community. The Gene Ontology Consortium (GOC) has expanded areas of the ontology such as cilia-related terms, cell-cycle terms and multicellular organism processes. We have also implemented new tools for generating ontology terms based on a set of logical rules making use of templates, and we have made efforts to increase our use of logical definitions. The GOC has a new and improved web site summarizing new developments and documentation, serving as a portal to GO data. Users can perform GO enrichment analysis, and search the GO for terms, annotations to gene products, and associated metadata across multiple species using the all-new AmiGO 2 browser. We encourage and welcome the input of the research community in all biological areas in our continued effort to improve the Gene Ontology.
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