Project description:Cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with B7 proteins CD80 and CD86. CTLA-4 is the first immune checkpoint targeted with a monoclonal antibody inhibitor. Checkpoint inhibitors have generated durable responses in many cancer patients, representing a revolutionary milestone in cancer immunotherapy. However, therapeutic efficacy is limited to a small portion of patients, and immune-related adverse events are noteworthy, especially for monoclonal antibodies directed against CTLA-4. Previously, small molecules have been developed to impair the CTLA-4: CD80 interaction; however, they directly targeted CD80 and not CTLA-4. In this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to target CTLA-4. We validated primary hits with biochemical, biophysical, immunological, and experimental animal assays. We then optimized lead compounds and obtained inhibitors with an inhibitory concentration of 1 micromole in disrupting the interaction between CTLA-4 and CD80. Unlike ipilimumab, these small molecules did not degrade CTLA-4. Several compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. This project supports an AI-based framework in designing small molecules targeting immune checkpoints for cancer therapy.
Project description:BackgroundThe management of acne requires the consideration of its severity; however, a universally adopted evaluation system for clinical practice is lacking. Artificial intelligence (AI) evaluation systems hold the promise of enhancing the efficiency and reproducibility of assessments. Artificial intelligence (AI) evaluation systems offer the potential to enhance the efficiency and reproducibility of assessments in this domain. While the identification of skin lesions represents a crucial component of acne evaluation, existing AI systems often overlook lesion identification or fail to integrate it with severity assessment. This study aimed to develop an AI-powered acne grading system and compare its performance with physician image-based scoring.MethodsA total of 1,501 acne patients were included in the study, and standardized pictures were obtained using the VISIA system. The initial evaluation involved 40 stratified sampled frontal photos assessed by seven dermatologists. Subsequently, the three doctors with the highest inter-rater agreement annotated the remaining 1,461 images, which served as the dataset for the development of the AI system. The dataset was randomly divided into two groups: 276 images were allocated for training the acne lesion identification platform, and 1,185 images were used to assess the severity of acne.ResultsThe average precision of our model for skin lesion identification was 0.507 and the average recall was 0.775. The AI severity grading system achieved good agreement with the true label (linear weighted kappa = 0.652). After integrating the lesion identification results into the severity assessment with fixed weights and learnable weights, the kappa rose to 0.737 and 0.696, respectively, and the entire evaluation on a Linux workstation with a Tesla K40m GPU took less than 0.1s per picture.ConclusionThis study developed a system that detects various types of acne lesions and correlates them well with acne severity grading, and the good accuracy and efficiency make this approach potentially an effective clinical decision support tool.
Project description:Computational docking is an instrumental method of the structural biology toolbox. Specifically, integrative modeling software, such as LightDock, arise as complementary and synergetic methods to experimental structural biology techniques. Ubiquitousness and accessibility are fundamental features to promote ease of use and to improve user experience. With this goal in mind, we have developed the LightDock Server, a web server for the integrative modeling of macromolecular interactions, along with several dedicated usage modes. The server builds upon the LightDock macromolecular docking framework, which has proved useful for modeling medium-to-high flexible complexes, antibody-antigen interactions, or membrane-associated protein assemblies. We believe that this free-to-use resource will be a valuable addition to the structural biology community and can be accessed online at: https://server.lightdock.org/.
Project description:We introduce HARMONI, a three-dimensional (3D) computer vision and audio processing method for analyzing caregiver-child behavior and interaction from observational videos. HARMONI operates at subsecond resolution, estimating 3D mesh representations and spatial interactions of humans, and adapts to challenging natural environments using an environment-targeted synthetic data generation module. Deployed on 500 hours from the SEEDLingS dataset, HARMONI generates detailed quantitative measurements of 3D human behavior previously unattainable through manual efforts or 2D methods. HARMONI identifies longitudinal trends in child-caregiver interaction, including child movement, body pose, dyadic touch, visibility, and conversational turns. The integrated visual and audio analysis further reveals multimodal trends, including associations between child conversational turns and movement. Open-sourced for large-scale analysis, HARMONI facilitates advancements in human development research. HARMONI achieves 63 to 80% consistency on key attributes with human annotators on SEEDLingS and 84 to 93% consistency on videos taken from a laboratory setting while achieving >100 times savings in time.
Project description:Background/objectivesCheckpoint inhibitors, which generate durable responses in many cancer patients, have revolutionized cancer immunotherapy. However, their therapeutic efficacy is limited, and immune-related adverse events are severe, especially for monoclonal antibody treatment directed against cytotoxic T-lymphocyte-associated protein 4 (CTLA-4), which plays a pivotal role in preventing autoimmunity and fostering anticancer immunity by interacting with the B7 proteins CD80 and CD86. Small molecules impairing the CTLA-4/CD80 interaction have been developed; however, they directly target CD80, not CTLA-4.Subjects/methodsIn this study, we performed artificial intelligence (AI)-powered virtual screening of approximately ten million compounds to identify those targeting CTLA-4. We validated the hits molecules with biochemical, biophysical, immunological, and experimental animal assays.ResultsThe primary hits obtained from the virtual screening were successfully validated in vitro and in vivo. We then optimized lead compounds and obtained inhibitors (inhibitory concentration, 1 micromole) that disrupted the CTLA-4/CD80 interaction without degrading CTLA-4.ConclusionsSeveral compounds inhibited tumor development prophylactically and therapeutically in syngeneic and CTLA-4-humanized mice. Our findings support using AI-based frameworks to design small molecules targeting immune checkpoints for cancer therapy.
Project description:In the wake of the largest-ever recorded outbreak of mpox in terms of magnitude and geographical spread in human history since May 2022, we innovatively developed an automated online sewage virus enrichment and concentration robot for disease tracking. Coupled with an artificial intelligence (AI) model, our research aims to estimate mpox cases based on the concentration of the monkeypox virus (MPXV) in wastewater. Our research has revealed a compelling link between the levels of MPXV in wastewater and the number of clinically confirmed mpox infections, a finding that is reinforced by the ability of our AI prediction model to forecast cases with remarkable precision, capturing 87 % of the data's variability. However, it is worth noting that this high precision in predictions may be related to the relatively high frequency of data acquisition and the relatively non-mobile isolated environment of the hospital itself. In conclusion, this study represents a significant step forward in our ability to track and respond to mpox outbreaks. It has the potential to revolutionize public health surveillance by utilizing innovative technologies for disease surveillance and prediction.
Project description:Background: Increased utilization of artificial intelligence (AI)-driven search and large language models by the lay and medical community requires us to evaluate the accuracy of AI responses to common hand surgery questions. We hypothesized that the answers to most hand surgery questions posed to an AI large language model would be correct. Methods: Using the topics covered in Green's Operative Hand Surgery 8th Edition as a guide, 56 hand surgery questions were compiled and posed to ChatGPT (OpenAI, San Francisco, CA). Two attending hand surgeons then independently reviewed ChatGPT's answers for response accuracy, completeness, and usefulness. A Cohen's kappa analysis was performed to assess interrater agreement. Results: An average of 45 of the 56 questions posed to ChatGPT were deemed correct (80%), 39 responses were deemed useful (70%), and 32 responses were deemed complete (57%) by the reviewers. Kappa analysis demonstrated "fair to moderate" agreement between the two raters. Reviewers disagreed on 11 questions regarding correctness, 16 questions regarding usefulness, and 19 questions regarding completeness. Conclusions: Large language models have the potential to both positively and negatively impact patient perceptions and guide referral patterns based on the accuracy, completeness, and usefulness of their responses. While most responses fit these criteria, more precise responses are needed to ensure patient safety and avoid misinformation. Individual hand surgeons and surgical societies must understand these technologies and interface with the companies developing them to provide our patients with the best possible care.