Discovery and Preclinical Pharmacology of INE963, a Potent and Fast-Acting Blood-Stage Antimalarial with a High Barrier to Resistance and Potential for Single-Dose Cures in Uncomplicated Malaria.

A series of 5-aryl-2-amino-imidazothiadiazole (ITD) derivatives were identified by a phenotype-based high-throughput screening using a blood stage Plasmodium falciparum (Pf) growth inhibition assay. A lead optimization program focused on improving antiplasmodium potency, selectivity against human kinases, and absorption, distribution, metabolism, excretion, and toxicity properties and extended pharmacological profiles culminated in the identification of INE963 (1), which demonstrates potent cellular activity against Pf 3D7 (EC50 = 0.006 μM) and achieves artemisinin-like kill kinetics in vitro with a parasite clearance time of \u3c24 h. A single dose of 30 mg/kg is fully curative in the Pf-humanized severe combined immunodeficient mouse model. INE963 (1) also exhibits a high barrier to resistance in drug selection studies and a long half-life (T1/2) across species. These properties suggest the significant potential for INE963 (1) to provide a curative therapy for uncomplicated malaria with short dosing regimens. For these reasons, INE963 (1) was progressed through GLP toxicology studies and is now undergoing Ph1 clinical trials

Modeling and Simulation of the Hysteretic Behavior of Concrete under Cyclic Tension–Compression Using the Smeared Crack Approach

Concrete structures under wind and earthquake loads will experience tensile and compressive stress reversals. It is very important to accurately reproduce the hysteretic behavior and energy dissipation of concrete materials under cyclic tension–compression for the safety evaluation of concrete structures. A hysteretic model for concrete under cyclic tension–compression is proposed in the framework of smeared crack theory. Based on the crack surface opening–closing mechanism, the relationship between crack surface stress and cracking strain is constructed in a local coordinate system. Linear loading–unloading paths are used and the partial unloading–reloading condition is considered. The hysteretic curves in the model are controlled by two parameters: the initial closing stress and the complete closing stress, which can be determined by the test results. Comparison with several experimental results shows that the model is capable of simulating the cracking process and hysteretic behavior of concrete. In addition, the model is proven to be able to reproduce the damage evolution, energy dissipation, and stiffness recovery caused by crack closure during the cyclic tension–compression. The proposed model can be applied to the nonlinear analysis of real concrete structures under complex cyclic loads

Co-creation of Social Innovation: Corporate Universities as Innovative Strategies for Chinese Firms to Engage with Society

Corporate social innovation is a novel, strategic means for enterprise to establish competitive advantage through collaboration with powerful stakeholders, like governments, where firms are simultaneously able to meet social needs and benefit themselves. There is, however limited empirical research investigating how such collaboration enables the co-creation of innovation between firms and society, particularly in emerging markets. In response, this paper takes corporate universities (CUs), a typical manifestation of corporate social innovation, as an example, and explores whether CUs encourage employees to engage in innovation and pro-environmental behaviors, thereby contributing to their firms and local communities in China. Using quantitative methods, we found that employees’ participation in CU training/education courses significantly affects employees’ innovation and environmentally-friendly behaviors in both work and life, and that it enhances their normative commitment (NC) to organizations. Moreover, this commitment mediates employees’ participation in the university program, in terms of both their innovation and pro-environmental behaviors. The main contribution of this paper is to enrich the innovation literature by suggesting a fresh, co-creation mechanism of social innovation between enterprise and government, while offering valuable first-hand evidence in a non-Western context. Our results allow policy makers and stakeholders to gain an in depth understanding of relevant issues

JAEGER – Hunting for Antimalarials with Generative Chemistry

Recent advances in generative modeling allow designing novel compounds through deep neural networks. One such neural network model, the Junction Tree Variational Auto- Encoder (JT-VAE), excels at proposing chemically valid structures. Based on JT-VAE, we built a generative modeling approach (JAEGER) for finding novel chemical matter with desired bioactivity. Using JAEGER, we designed compounds to inhibit malaria. To prioritize the compounds for synthesis, we used the in-house Profile-QSAR (pQSAR) program, a massively-multitask bioactivity model based on 12,000 Novartis assays. Based on the pQSAR activity predictions, we selected, synthesized, and experimentally profiled two compounds. Both compounds exhibited low nanomolar activity in a malaria proliferation assay as well as a biochemical assay measuring activity against PI(4)K, which is an essential kinase that regulates intracellular development in malaria. The compounds also showed low activity in a cytotoxicity assay. Our findings show that JAEGER is a viable approach for finding novel active compounds for drug discovery