The functional motions and related key residues behind the uncoating of coxsackievirus A16.

The coxsackievirus A16 (CVA16) is a highly contagious virus that causes the hand, foot, and mouth disease, which seriously threatens the health of children. At present, there are still no available antiviral drugs or effective treatments against the infection of CVA16, and thus it is of great significance to develop anti-CVA16 vaccines. However, the intrinsic uncoating property of the capsid may destroy the neutralizing epitopes and influence its immunogenicity, which hinders the vaccine developments. In the present work, the functional-quantity-based elastic network model analysis method developed by our group was extended to combine with group theory to investigate the uncoating motions of the CVA16 capsid, and then the functionally key residues controlling the uncoating motions were identified by our functional-quantity-based perturbation method. Several motion modes encoded in the topological structure of the capsid were revealed to be responsible for the uncoating of CVA16 particle. These modes predominantly contribute to the fluctuation of the gyration radius of the capsid. Then, by using the perturbation method, four clusters of key sites involved in the uncoating motions were identified, whose perturbations induce significant changes in the fluctuation of the gyration radius. These key residues are mainly located at the 2-fold channels, the quasi 3-fold channels, the bottom of the canyons, and the inter-subunit interfaces around the 3-fold axes. Our studies are helpful for better understanding the uncoating mechanism of the CVA16 capsid and provide potential target sites to prevent the uncoating motions, which is valuable for the vaccine design against CVA16.

Impact of gamma-ray radiation-induced photodarkening on mode instability degradation of an ytterbium-doped fiber amplifier.

The laser performance of a high-power ytterbium-doped fiber amplifier is mainly hindered by the onset of mode instability. In this work, the slope efficiency and mode instability threshold of the ytterbium-doped fiber under various gamma-ray radiation doses have been measured. Experimental results reveal that gamma-ray radiation-induced photodarkening degrades mode instability severely, and gamma-ray radiation-induced mode instability degradation can be partly bleached by hours of pump-light injection. It is shown that gamma-ray radiation-induced photodarkening results in a steep reduction of slope efficiency and mode instability threshold; moreover, the entire irradiated fiber can be partly bleached by hours of pump-light injection and exhibits both time and gamma-ray radiation-dose saturation properties. The experimental results indicate that mode instability mitigation can be partly realized by pump-light injection and implies photodarkening suppression is beneficial for TMI mitigation, which is very promising for the advancement of high-power fiber lasers.

Leonurine hydrochloride inhibits osteoclastogenesis and prevents osteoporosis associated with estrogen deficiency by inhibiting the NF-κB and PI3K/Akt signaling pathways.

Osteoclasts, the primary bone resorbing cells, are responsible for destructive bone diseases such as postmenopausal osteoporosis, rheumatoid arthritis, and periodontitis. Many plant-derived traditional medicines that might suppress the formation and/or function of osteoclasts are promising treatments for osteoclast-related diseases. In this study, we investigated the effects of leonurine hydrochloride (LH) on receptor activator NF-κB ligand (RANKL)-induced osteoclastogenesis and ovariectomy-induced bone loss. LH is a synthetic chemical compound based on the structure of leonurine, which is found in motherwort and has been reported to exhibit phytoestrogenic activity. In RAW 264.7 cells and mouse bone marrow monocytes (BMMs), LH suppressed RANKL-induced osteoclastogenesis and actin ring formation in a dose-dependent manner. LH targeted RANKL-induced osteoclastogenesis and bone resorption at an early stage. Molecular analysis demonstrated that LH attenuated RANKL-induced NF-κB signaling by inhibiting the phosphorylation and degradation of IκBα and NF-κB p65 nuclear translocation. LH inhibited the RANK-TRAF6 association triggered by RANKL binding and the phosphatidylinositol 3-kinase (PI3K)/Akt axis, without significantly affecting the extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinase (MAPK) and AP-1 signaling pathways. LH attenuated the RANKL-stimulated expression of osteoclast-related genes including NFATc1, tartrate resistant acid phosphatase (TRAP), cathepsin K, and osteoclast-associated receptor (OSCAR). Consistent with the in vitro results, LH administration attenuated osteoclast activity, thus preventing bone loss caused by estrogen deficiency in mice. In this study, LH suppressed RANKL-induced osteoclastogenesis via RANK-TRAF6, NF-κB, and PI3K/Akt signaling. These data provide the first evidence that LH might be a promising therapeutic compound to treat osteoclast-related diseases, such as osteoporosis.