[SLFN14 inhibits LINE-1 transposition activity].

Long interspersed nuclear element-1 (LINE-1) is the only active autonomous transposon in the human genome. Its transposition frequently induces host genome instability, leading to a variety of genetic diseases, including cancers. The host factors play important roles in inhibiting LINE-1 retrotransposition. As an important component of the immune system, the host factor SLFN14 has antiviral activity. Our laboratory shows that SLFN14 possesses potent inhibitory activity against LINE-1 retrotransposition. To explore the potential mechanism of SLFN14 inhibition, we analyzed its effects on transcription, translation, reverse transcription and insertion in the LINE-1 replication cycle. We confirmed that SLFN14 could suppress the LINE-1 mRNA level by affecting its transcription and degradation, thereby diminishing the protein and cDNA levels of LINE-1, which eventually block the LINE-1 retrotransposition. Further, by mapping the active domains of SLFN14, we found its inhibitory activity on LINE-1 being closely related to its endoribonuclease and ribosome binding domains. These results demonstrate the mechanism of SLFN14 in regulating LINE-1 replication, which further provide new insights for improving the regulation network of host factors for controlling genomic instability caused by LINE-1 replication.

[Establishment and application of a drug screening model for anti-prostate cancer agents targeting androgen receptor].

Androgen receptor(AR) plays an important role in the maintenance of prostate function and development of prostate cancer. AR is the key target in the therapy of prostate cancer. In this study, a cell-based screening assay was established by dual-luciferase reporter system to analyze the activity of AR. In the screening assay, we detected the anti-prostate cancer activities of rhodiola root extract, wild kiwifruit root extract and tripterygium wilfordii root extract, which may provide a new strategy for the treatment of prostate cancer.

[The sensitivity of transmitted/founder HIV-1 to anti-HIV drugs].

The majority of mucosal HIV-1 infection is initially established by a few HIV-1 viral variants, followed by the development of overt systemic infection, and these viral variants are known as transmitted/ founder viruses(T/F viruses). Investigation of the sensitivity of T/F virus to different anti-HIV-1 drugs will provide the best strategies of pre-exposure prophylaxis(Pr EP) for high-risk groups of HIV-infected patients. Herein we constructed for the first time, a luciferase reporter system for HIV-1 T/F viruses, and then compared the drug sensitivity between T/F viruses and chronic infection virus. The result showed that the 50% inhibitory concentration (IC(50)) of nucleoside reverse transcriptase inhibitors(NRTIs), integrase inhibitors(INIs) and protease inhibitors(PIs) were not significantly different between the T/F viruses and chronic infection viruses of the same subtype(P < 0.05), while non-nucleoside reverse transcriptase inhibitors(NNRTIs) showed a moderate resistance to T/F viruses, with a significant increase in IC50(P < 0.05). The conclusion suggests that when patients are in high-risk or in the acute infection of HIV-1, NNRTIs should be avoided in the first-line antiretroviral therapy regimens.

Progress and challenges in the use of latent HIV-1 reactivating agents.

Highly active antiretroviral therapy (HAART) can effectively suppress the replication of human immunodeficiency virus-1 (HIV-1) and block disease progression. However, chronic HIV-1 infection remains incurable due to the persistence of a viral reservoir, including the transcriptionally silent provirus in CD4(+) memory T cells and the sanctuary sites that are inaccessible to drugs. Reactivation and the subsequent elimination of latent virus through virus-specific cytotoxic effects or host immune responses are critical strategies for combating the disease. Indeed, a number of latency reactivating reagents have been identified through mechanism-directed approaches and large-scale screening, including: (1) histone deacetylase inhibitors (HDACi); (2) cytokines and chemokines; (3) DNA methyltransferase inhibitors (DNMTI); (4) histone methyltransferase inhibitors (HMTI); (5) protein kinase C (PKC) activators; (6) P-TEFb activators; and (7) unclassified agents, such as disulfram. They have proved to be efficacious in latent cell line models and CD4(+) T lymphocytes from HIV-1-infected patients. This review comprehensively summarizes the recent progress and relative challenges in this field.

[Identification and characterization of HIV-1 transmitted /founder viruses].

During the spread of human immunodeficiency virus type 1 (HIV-1) in the mucosa, the entire genetic diversity of the viruses is significantly reduced. The vast majority of HIV-1 mucosal infections are established by one or a few viruses and ultimately develop into systemic infections, thus the initial virus is called transmitted/founder virus (T/F virus). The study of T/F virus will benefit understanding its key characteristics resulting in successful viral replication in the new host body, which may provide novel strategies for the development of AIDS vaccines, pre-exposure prophylaxis and other therapeutic interventions. In this review, we summarize the discovery and evolutionary characteristics of T/F virus as well as early immune response after HIV-1 infection, which will establish the basis to explore the features of T/F viruses.

Genetic variance in the HIV-1 founder virus Vpr affects its ability to induce cell cycle G2arrest and cell apoptosis.

In the event of acute infection, only a few HIV-1 viral variants can establish the initial productive clinical infection, and these viral variants are known as transmitted/founder viruses (T/F viruses). As one of the accessory proteins of HIV-1, viral protein R (Vpr) plays an important role in viral replication. Therefore, the characterization of T/F virus Vpr is beneficial to understand how virus replicates in a new host. In this study, flow cytometry was used to analyze the effect of G2arrest and cell apoptosis induced by the T/F virus Vpr and the chronic strain MJ4 Vpr. The results showed that the ability of T/F virus ZM246 Vpr and ZM247 Vpr inducing G2arrest and cell apoptosis are more potent than the MJ4 Vpr. The comparison of protein sequences indicated that the amino acids of 77, 85 and 94 contain high freqency mutations, suggesting that these sites may be involved in inducing G2arrest and cell apoptosis. Taken together, our work suggests that in acute infections, T/F viruses increase the capacity of G2arrest and cell apoptosis and promote viral replication and transmission in a new host by Vpr genetic mutation.

[Total trans-oral endoscopic thyroidectomy and cervical lymphadenectomy: a human cadavers surgery study].

OBJECTIVE: To find an approach for trans-oral endoscopic thyroidectomy (TOET) and cervical lymphadenectomy using conventional endoscopic surgical instruments on frozen fresh cadavers. METHODS: Six frozen fresh cadavers were used in three groups of trans-oral trocar installation experiments: oral vestibule installation, sublingual region installation, and combined bi-vestibular and sublingual installation. TOET (with pretrachealis method to thyroid fixation removal) and cervical lymphadenectomy were performed experiments on another 6 frozen fresh cadavers using the best access approach found in the aforementioned experiments. RESULTS: In oral vestibule trocar installations, the trocars caused large lacerated wound and damaged air tightness. In sublingual installations, only one trocar could be installed in the sublingual area because the space in sublingual area was limited. In combined bi-vestibular and sublingual installations, no gland, vessel or nerve was damaged. Combined bi-vestibular and sublingual access were selected as the surgical approach on the basic of analysis the merits of each approach. TOET and cervical lymphadenectomy in area III, IV, VI, VII were performed without making any accessory damage through combined bi-vestibular and sublingual access approach. CONCLUSIONS: TOET is feasible. Combined bi-vestibular and sublingual approach is available for TOET. Part of the cervical lymph nodes could be resected. Pretrachealis approach to thyroid fixation removal can still be used.

Construction and characterization of an infectious cDNA clone of enterovirus type 71 subgenotype C4.

Enterovirus 71 (EV71) is the major causative agent of hand, foot, and mouth disease and induces fatal neurological complications. In recent years, this virus has become a major threat to public health in the Asia-Pacific region, while no effective antiviral therapies and vaccines are currently available. In this study, we constructed and characterized for the first time an infectious full-length EV71 cDNA clone derived from the SHZH98 strain, which was the first subgenotype C4 strain isolated in China. Our data demonstrate that the rescued EV71 viruses exhibited growth kinetics in vitro and morphologies similar to those of the BrCr-TR strain and reached a maximum titer of 10(7.5) TCID50/ml. Although the rescued viruses were able to infect suckling mice, no typical symptoms of EV71 infection were observed for up to 18 days post-inoculation. Taken together our research provides an important tool to study the epidemic strains of EV71 in the Asia-Pacific region and promote the development of vaccines.