CRISPR-Cas9 In Vivo Gene Editing for Transthyretin Amyloidosis

BACKGROUND: Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS: After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS: Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS: In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.

Application of Cardio-Forecasting for Evaluation of Human—Operator Performance

The paper presents the results of the development of the cardio-forecasting technology, which introduces a new method to monitor the state of human-operator, which is characteristic for the given production conditions and for individual operators, to predict the moment of exhaustion of his/her working capacity. The work aims to demonstrate the unique, distinctive features of the cardio-forecasting technology for predicting an individual limit of his/her working capacity for each person. A unique methodology for predicting individually for each person the moment when he/she reaches the limit of his/her working capacity is based on a spectral analysis of a human phonocardiogram in order to isolate the frequency component located at the heart contraction frequency. The trend of the amplitude of this component is approximated by its model; consequently, the coefficients of the trend model are determined. They include the operator’s operating time until his/her working capacity is exhausted. A methodology for predicting the moment when he/she reaches the limit of his/her working capacity for each person individually and assessment based on this degree of criticality of their condition will be realized as a software application for smartphones using the Android operating system

USE OF VIBRODIAGNOSTICS TO PREDICT PHENOMENA IN SERIAL AUTOMOTIVE PRODUCTION

The paper discusses the use of vibrodiagnostics in automotive production. Describes the Fast Fourier Transformation and its importance in evaluating the measured values. It focuses on the process of honing the toothing of shafts used in series-produced gearboxes. Describes 3 different states of amplitude with consideration to the set limit. In the first state, all production criteria are met. In the second state, the limit is exceeded and the specific error and its impact on the continuation of production are described. The third state describes the extreme crossing of the limit and the consequences for this state. Finally, the importance and practicality of the method for predicting production conditions are summarized.</jats:p