Fused in sarcoma regulates DNA replication timing and kinetics.

Fused in sarcoma (FUS) encodes an RNA-binding protein with diverse roles in transcriptional activation and RNA splicing. While oncogenic fusions of FUS and transcription factor DNA-binding domains are associated with soft tissue sarcomas, dominant mutations in FUS can cause amyotrophic lateral sclerosis. FUS has also been implicated in genome maintenance. However, the underlying mechanisms of its actions in genome stability are unknown. Here, we applied gene editing, functional reconstitution, and integrated proteomics and transcriptomics to illuminate roles for FUS in DNA replication and repair. Consistent with a supportive role in DNA double-strand break repair, FUS-deficient cells exhibited subtle alterations in the recruitment and retention of double-strand break-associated factors, including 53BP1 and BRCA1. FUS-/- cells also exhibited reduced proliferative potential that correlated with reduced speed of replication fork progression, diminished loading of prereplication complexes, enhanced micronucleus formation, and attenuated expression and splicing of S-phase-associated genes. Finally, FUS-deficient cells exhibited genome-wide alterations in DNA replication timing that were reversed upon re-expression of FUS complementary DNA. We also showed that FUS-dependent replication domains were enriched in transcriptionally active chromatin and that FUS was required for the timely replication of transcriptionally active DNA. These findings suggest that alterations in DNA replication kinetics and programming contribute to genome instability and functional defects in FUS-deficient cells.

Synthesizing time-series wound prognosis factors from electronic medical records using generative adversarial networks.

Wound prognostic models not only provide an estimate of wound healing time to motivate patients to follow up their treatments but also can help clinicians to decide whether to use a standard care or adjuvant therapies and to assist them with designing clinical trials. However, collecting prognosis factors from Electronic Medical Records (EMR) of patients is challenging due to privacy, sensitivity, and confidentiality. In this study, we developed time series medical generative adversarial networks (GANs) to generate synthetic wound prognosis factors using very limited information collected during routine care in a specialized wound care facility. The generated prognosis variables are used in developing a predictive model for chronic wound healing trajectory. Our novel medical GAN can produce both continuous and categorical features from EMR. Moreover, we applied temporal information to our model by considering data collected from the weekly follow-ups of patients. Conditional training strategies were utilized to enhance training and generate classified data in terms of healing or non-healing. The ability of the proposed model to generate realistic EMR data was evaluated by TSTR (test on the synthetic, train on the real), discriminative accuracy, and visualization. We utilized samples generated by our proposed GAN in training a prognosis model to demonstrate its real-life application. Using the generated samples in training predictive models improved the classification accuracy by 6.66-10.01% compared to the previous EMR-GAN. Additionally, the suggested prognosis classifier has achieved the area under the curve (AUC) of 0.875, 0.810, and 0.647 when training the network using data from the first three visits, first two visits, and first visit, respectively. These results indicate a significant improvement in wound healing prediction compared to the previous prognosis models.

Evidence-based Potential Therapeutic Applications of Cannabinoids in Wound Management.

BACKGROUND: Although wound management is a major component of all domains of healthcare, conventional therapeutics have numerous limitations. The endocannabinoid system of the skin, one of the major endogenous systems, has recently been connected to wound healing. Cannabinoids and their interactions with the endogenous chemical signaling system may be a promising therapeutic option because they address some of the fundamental pathways for physiologic derangement that underpin chronic integumentary wounds. RECENT ADVANCES: The therapeutic applications of cannabinoids are increasing because of their legalization and resulting market expansion. Recently, their immunosuppressive and anti-inflammatory properties have been explored for the treatment of wounds that are not effectively managed by conventional medicines. CRITICAL ISSUES: Failure to manage wounds effectively is associated with reduced quality of life, disability, mortality, and increased healthcare expenditures. Therapeutic options that can manage wounds effectively and efficiently are needed. In this review, the authors summarize recent advances on the use of cannabinoids to treat skin disorders with an emphasis on wound management. FUTURE DIRECTIONS: Effective wound management requires medicines with good therapeutic outcomes and minimal adverse effects. Despite the promising results of cannabinoids in wound management, further controlled clinical studies are required to establish the definitive role of these compounds in the pathophysiology of wounds and their usefulness in the clinical setting.