ABSTRACT
Inhibitor discovery for emerging drug-target proteins is challenging, especially when target structure or active molecules are unknown. Here, we experimentally validate the broad utility of a deep generative framework trained at-scale on protein sequences, small molecules, and their mutual interactions-unbiased toward any specific target. We performed a protein sequence-conditioned sampling on the generative foundation model to design small-molecule inhibitors for two dissimilar targets: the spike protein receptor-binding domain (RBD) and the main protease from SARS-CoV-2. Despite using only the target sequence information during the model inference, micromolar-level inhibition was observed in vitro for two candidates out of four synthesized for each target. The most potent spike RBD inhibitor exhibited activity against several variants in live virus neutralization assays. These results establish that a single, broadly deployable generative foundation model for accelerated inhibitor discovery is effective and efficient, even in the absence of target structure or binder information.
Subject(s)
Antibodies, Viral , COVID-19 , Humans , Antibodies, Viral/chemistry , SARS-CoV-2/metabolism , Protein Binding , Amino Acid SequenceABSTRACT
To provide the best available evidence-based care to their patients, advanced practitioners (APs) must become proficient in genomic competencies and remain informed regarding the availability of pharmacogenomic tests. Databases, such as the Centers for Disease Control and Prevention's "Genomic Testing," provide guidance about pharmacogenomic testing, but many APs are not aware of these resources. This study employed a quasi-experimental pretest/posttest design using a convenience sample of APs in a large clinical outpatient breast cancer clinic to assess the knowledge base, beliefs, attitudes, and barriers regarding pharmacogenomic testing among front-line APs and increase knowledge through a targeted educational intervention. The objectives of the educational intervention were to (1) increase knowledge of the clinical indication for testing; (2) increase collaboration among the interprofessional team; and (3) identify correctly when the plan of care should be modified based on pharmacogenomic test results to optimize patient outcomes. Responses showed that these oncology APs possess a strong foundation in genetics and support the addition of new pharmacogenomic tests to their practice.
ABSTRACT
Objective. The objective of this systematic review and meta-analysis was to assess the efficacy of auricular therapy by including a sham therapy control group. Methods. Relevant, randomized clinical trials (RCTs) were identified by searching medical related databases from, depending on journal, 1900 (at the earliest) to 1994 (at the latest) through May 2013. The outcome measure was a pain intensity score. Results. Twenty-two RCTs were identified and 13 RCTs were included for meta-analysis. In these studies, auricular therapy provided significant pain relief when compared to a sham or control group. The overall standardized mean differences (SMD) was 1.59 (95% CI [-2.36, -0.82]) (13 trials, total subject numbers = 806), indicating that, on average, the mean decrease in pain score for auricular therapy group was 1.59 standard deviations greater than the mean decrease for the sham control. In terms of the efficacy of the different treatment methods, auricular acupressure boasts the largest strength of evidence for pain relief, followed by auricular acupuncture. Electroacupuncture stimulation did not show significant evidence for efficacy, which may be due to the small sample size (i.e., only 19 subjects were included). Conclusion. Further large-scale RCTs are needed to determine the efficacy of auricular therapy for pain.
ABSTRACT
This prospective, randomized clinical trial (RCT) pilot study was designed to (1) assess the feasibility and tolerability of an easily administered, auricular point acupressure (APA) intervention and (2) provide an initial assessment of effect size as compared to a sham treatment. Thirty-seven subjects were randomized to receive either the real or sham APA treatment. All participants were treated once a week for 4 weeks. Self-report measures were obtained at baseline, weekly during treatment, at end-of-intervention (EOI), and at a 1-month follow-up. A dropout rate of 26% in the real APA group and 50% in the sham group was observed. The reduction in worst pain from baseline to EOI was 41% for the real and 5% for the sham group with a Cohen's effect size of 1.22 (P < 0.00). Disability scores on the Roland Morris Disability Questionnaire (RMDQ) decreased in the real group by 29% and were unchanged in the sham group (+3%) (P < 0.00). Given the high dropout rate, results must be interpreted with caution; nevertheless, our results suggest that APA may provide an inexpensive and effective complementary approach for the management of back pain in older adults, and further study is warranted.
