RESUMO
Phenotypic assays have become an established approach to drug discovery. Greater disease relevance is often achieved through cellular models with increased complexity and more detailed readouts, such as gene expression or advanced imaging. However, the intricate nature and cost of these assays impose limitations on their screening capacity, often restricting screens to well-characterized small compound sets such as chemogenomics libraries. Here, we outline a cheminformatics approach to identify a small set of compounds with likely novel mechanisms of action (MoAs), expanding the MoA search space for throughput limited phenotypic assays. Our approach is based on mining existing large-scale, phenotypic high-throughput screening (HTS) data. It enables the identification of chemotypes that exhibit selectivity across multiple cell-based assays, which are characterized by persistent and broad structure activity relationships (SAR). We validate the effectiveness of our approach in broad cellular profiling assays (Cell Painting, DRUG-seq, and Promotor Signature Profiling) and chemical proteomics experiments. These experiments revealed that the compounds behave similarly to known chemogenetic libraries, but with a notable bias toward novel protein targets. To foster collaboration and advance research in this area, we have curated a public set of such compounds based on the PubChem BioAssay dataset and made it available for use by the scientific community.
Assuntos
Descoberta de Drogas , Ensaios de Triagem em Larga Escala , Bibliotecas de Moléculas Pequenas , Descoberta de Drogas/métodos , Ensaios de Triagem em Larga Escala/métodos , Quimioinformática/métodos , Bibliotecas de Moléculas Pequenas/química , Relação Estrutura-AtividadeRESUMO
This article establishes a general equivalence between discrete choice and rational inattention models. Matejka and McKay (2015) showed that when information costs are modeled using the Shannon entropy, the choice probabilities in the rational inattention (RI) model take the multinomial logit form. We show that, for one given prior over states, RI choice probabilities may take the form of any additive random utility discrete choice model (ARUM) when the information cost is a Bregman information, a class defined in this article. The prior information of the rationally inattentive agent is summarized in a constant vector of utilities in the corresponding ARUM.
RESUMO
AIM: The aim of this study was to determine the prevalence of dental developmental disturbances in long-term survivors of childhood malignancies in New Zealand children. This study reports associations with potential risk factors to inform oncologists and dentists of the likelihood of dental abnormalities. METHODS: The study population was children aged 14-16 years old who were diagnosed with cancer prior to 10 years of age. A total of 156 children were eligible, of which 59 participated in this study. The indices used in this study were Holtta's Defect Index (HDI), and Oral Health Impact Profile-14 (OHIP-14). RESULTS: The prevalence of agenesis was 15.3%, microdontia 6.8% and root abnormalities 32.2%. Cyclophosphamide equivalent doses above 8,000mg/m2, stem cell therapy (SCT), and head and neck radiation therapy (HNRT) were associated with a higher mean number of teeth missing due to agenesis. SCT and HNRT were associated with a higher total HDI. A binary logistic regression was carried out to determine the odds of agenesis and found that HNRT was the main contributing factor (OR=7.7, p-value=0.04). The linear regression model found that dactinomycin and agenesis correlated with the largest mean OHIP-14. CONCLUSION: This study found that childhood cancer survivors in New Zealand had a high prevalence of developmental dental abnormalities and it identified potential risk factors related to their cancer treatment. Inequitable access to oral rehabilitation for this patient group argues for a mechanism for consistent improved access to publicly funded dental care across district health boards in New Zealand.
Assuntos
Anodontia , Sobreviventes de Câncer/estatística & dados numéricos , Neoplasias , Adolescente , Anodontia/complicações , Anodontia/epidemiologia , Antineoplásicos Alquilantes/efeitos adversos , Antineoplásicos Alquilantes/uso terapêutico , Estudos Transversais , Ciclofosfamida/efeitos adversos , Ciclofosfamida/uso terapêutico , Feminino , Humanos , Masculino , Neoplasias/complicações , Neoplasias/epidemiologia , Neoplasias/terapia , Nova Zelândia , Prevalência , Radioterapia/efeitos adversos , Transplante de Células-Tronco/efeitos adversosRESUMO
OBJECTIVES: The aims of this study were to investigate (1) the jaw-opening forces in different stages of jaw-opening, and determine the correlation among maximum jaw-opening force, maximum jaw-opening, and parameters such as age, height, weight, and gender, (2) the energy expenditure during jaw-opening, and (3) the jaw-opening patterns in adults. DESIGN: This was a cross-sectional study. The sample consisted of 87 participants were recruited from Dunedin, New Zealand. Jaw-opening forces were measured using an adjustable, rigid extra-oral device connected to a 1000 N load cell. MAIN RESULTS: Outcomes were highly skewed. The median (IQR) value of maximum jaw-opening was 48 mm (8 mm). The median of maximum jaw-opening force (40.0 N) was higher than jaw-opening force at maximum jaw-opening (35.2 N) (P < 0.01). The median (IQR) of the work was 1.30 J (1.28 J), ranging from 0.38 J to 4.03 J. The median of maximum jaw-opening force and work was higher in males (54.8 N; 1.22 J) than females (33.5 N; 0.74 J) (P < 0.05). Four jaw-opening force patterns (Pattern 1, 2, 3 and 4) were fitted and generated using Origin Pro software. CONCLUSION: A wide range of variation in jaw-opening force and work was observed, and they displayed a non-parametric, highly skewed distributions. The maximum jaw-opening force did not correspond to the maximum jaw-opening. Further studies could explore the potential association among the jaw-opening force pattern, the work of jaw-opening and TMJ diseases.