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The COVID-19 pandemic caused by the SARS-CoV-2 virus continually poses serious threats to global public health. The main protease (Mpro) of SARS-CoV-2 plays a central role in viral replication. We designed and synthesized 32 new bicycloproline-containing Mpro inhibitors derived from either Boceprevir or Telaprevir, both of which are approved antivirals. All compounds inhibited SARS-CoV-2 Mpro activity in vitro with IC50 values ranging from 7.6 to 748.5 nM. The co-crystal structure of Mpro in complex with MI-23, one of the most potent compounds, revealed its interaction mode. Two compounds (MI-09 and MI-30) showed excellent antiviral activity in cell-based assays. In a SARS-CoV-2 infection transgenic mouse model, oral or intraperitoneal treatment with MI-09 or MI-30 significantly reduced lung viral loads and lung lesions. Both also displayed good pharmacokinetic properties and safety in rats.

ALICE is the heavy-ion experiment at the CERN Large Hadron Collider. The experiment continuously took data during the first physics campaign of the machine from fall 2009 until early 2013, using proton and lead-ion beams. In this paper we describe the running environment and the data handling procedures, and discuss the performance of the ALICE detectors and analysis methods for various physics observables.

Sandwich-structured BaTiO3 /poly(vinylidene fluoride) (PVDF) nanocomposites are successfully prepared by the solution-casting method layer by layer. They possess both high breakdown strength and large dielectric polarization simultaneously. An ultra-high energy-storage density of 18.8 J cm(-3) can be achieved by adjusting the volume fraction of ceramic fillers: this is almost three times larger than that of pure PVDF.

FOXO3a is a member of the FOXO subfamily of forkhead transcription factors that mediate a variety of cellular processes including apoptosis, proliferation, cell cycle progression, DNA damage and tumorigenesis. It also responds to several cellular stresses such as UV irradiation and oxidative stress. The function of FOXO3a is regulated by a complex network of processes, including post-transcriptional suppression by microRNAs (miRNAs), post-translational modifications (PTMs) and protein–protein interactions. FOXO3a is widely implicated in a variety of diseases, particularly in malignancy of breast, liver, colon, prostate, bladder, and nasopharyngeal cancers. Emerging evidences indicate that FOXO3a acts as a tumor suppressor in cancer. FOXO3a is frequently inactivated in cancer cell lines by mutation of the FOXO3a gene or cytoplasmic sequestration of FOXO3a protein. And its inactivation is associated with the initiation and progression of cancer. In experimental studies, overexpression of FOXO3a inhibits the proliferation, tumorigenic potential, and invasiveness of cancer cells, while silencing of FOXO3a results in marked attenuation in protection against tumorigenesis. The role of FOXO3a in both normal physiology as well as in cancer development have presented a great challenge to formulating an effective therapeutic strategy for cancer. In this review, we summarize the recent findings and overview of the current understanding of the influence of FOXO3a in cancer development and progression.