Click: Controllable Text Generation with Sequence Likelihood Contrastive Learning

It has always been an important yet challenging problem to control language models to avoid generating texts with undesirable attributes, such as toxic language and unnatural repetition. We introduce Click for controllable text generation, which needs no modification to the model architecture and facilitates out-of-the-box use of trained models. It employs a contrastive loss on sequence likelihood, which fundamentally decreases the generation probability of negative samples (i.e., generations with undesirable attributes). It also adopts a novel likelihood ranking-based strategy to construct contrastive samples from model generations. On the tasks of language detoxification, sentiment steering, and repetition reduction, we show that Click outperforms strong baselines of controllable text generation and demonstrate the superiority of Click's sample construction strategy.Comment: Findings of ACL 202

Time-domain simulation of ultrasound propagation with fractional Laplacians for lossy-medium biological tissues with complicated geometries

Simulations of ultrasound wave propagation inside biological tissues have a wide range of practical applications. In previous studies, wave propagation equations in lossy biological media are solved either with convolutions, which consume a large amount of memory, or with pseudo-spectral methods, which cannot handle complicated geometries effectively. The approach described in the paper employed a fractional central difference method (FCD), combined with the immersed boundary (IB) method for the finite-difference, time-domain simulation. The FCD method can solve the fractional Laplace terms in Chen and Holm’s lossy-medium equations directly in the physical domain without integral transforms. It also works naturally with the IB method, which enables a simple Cartesian-type grid mesh to be used to solve problems with complicated geometries. The numerical results agree very well with the analytical solutions for frequency power-law attenuation lossy mediaThis research is partly supported by the U.S. Army under a cooperative Agreement No. W911NF-14-2-007

ZIKV infection activates the IRE1-XBP1 and ATF6 pathways of unfolded protein response in neural cells.

BACKGROUND: Many viruses depend on the extensive membranous network of the endoplasmic reticulum (ER) for their translation, replication, and packaging. Certain membrane modifications of the ER can be a trigger for ER stress, as well as the accumulation of viral protein in the ER by viral infection. Then, unfolded protein response (UPR) is activated to alleviate the stress. Zika virus (ZIKV) is a mosquito-borne flavivirus and its infection causes microcephaly in newborns and serious neurological complications in adults. Here, we investigated ER stress and the regulating model of UPR in ZIKV-infected neural cells in vitro and in vivo. METHODS: Mice deficient in type I and II IFN receptors were infected with ZIKV via intraperitoneal injection and the nervous tissues of the mice were assayed at 5 days post-infection. The expression of phospho-IRE1, XBP1, and ATF6 which were the key markers of ER stress were analyzed by immunohistochemistry assay in vivo. Additionally, the nuclear localization of XBP1s and ATF6n were analyzed by immunohistofluorescence. Furthermore, two representative neural cells, neuroblastoma cell line (SK-N-SH) and astrocytoma cell line (CCF-STTG1), were selected to verify the ER stress in vitro. The expression of BIP, phospho-elF2α, phospho-IRE1, and ATF6 were analyzed through western blot and the nuclear localization of XBP1s was performed by confocal immunofluorescence microscopy. RT-qPCR was also used to quantify the mRNA level of the UPR downstream genes in vitro and in vivo. RESULTS: ZIKV infection significantly upregulated the expression of ER stress markers in vitro and in vivo. Phospho-IRE1 and XBP1 expression significantly increased in the cerebellum and mesocephalon, while ATF6 expression significantly increased in the mesocephalon. ATF6n and XBP1s were translocated into the cell nucleus. The levels of BIP, ATF6, phospho-elf2α, and spliced xbp1 also significantly increased in vitro. Furthermore, the downstream genes of UPR were detected to investigate the regulating model of the UPR during ZIKV infection in vitro and in vivo. The transcriptional levels of atf4, gadd34, chop, and edem-1 in vivo and that of gadd34 and chop in vitro significantly increased. CONCLUSION: Findings in this study demonstrated that ZIKV infection activates ER stress in neural cells. The results offer clues to further study the mechanism of neuropathogenesis caused by ZIKV infection

SUMO Modification Stabilizes Enterovirus 71 Polymerase 3D To Facilitate Viral Replication.

Accumulating evidence suggests that viruses hijack cellular proteins to circumvent the host immune system. Ubiquitination and SUMOylation are extensively studied posttranslational modifications (PTMs) that play critical roles in diverse biological processes. Cross talk between ubiquitination and SUMOylation of both host and viral proteins has been reported to result in distinct functional consequences. Enterovirus 71 (EV71), an RNA virus belonging to the family Picornaviridae, is a common cause of hand, foot, and mouth disease. Little is known concerning how host PTM systems interact with enteroviruses. Here, we demonstrate that the 3D protein, an RNA-dependent RNA polymerase (RdRp) of EV71, is modified by small ubiquitin-like modifier 1 (SUMO-1) both during infection and in vitro Residues K159 and L150/D151/L152 were responsible for 3D SUMOylation as determined by bioinformatics prediction combined with site-directed mutagenesis. Also, primer-dependent polymerase assays indicated that mutation of SUMOylation sites impaired 3D polymerase activity and virus replication. Moreover, 3D is ubiquitinated in a SUMO-dependent manner, and SUMOylation is crucial for 3D stability, which may be due to the interplay between the two PTMs. Importantly, increasing the level of SUMO-1 in EV71-infected cells augmented the SUMOylation and ubiquitination levels of 3D, leading to enhanced replication of EV71. These results together suggested that SUMO and ubiquitin cooperatively regulated EV71 infection, either by SUMO-ubiquitin hybrid chains or by ubiquitin conjugating to the exposed lysine residue through SUMOylation. Our study provides new insight into how a virus utilizes cellular pathways to facilitate its replication. IMPORTANCE: Infection with enterovirus 71 (EV71) often causes neurological diseases in children, and EV71 is responsible for the majority of fatalities. Based on a better understanding of interplay between virus and host cell, antiviral drugs against enteroviruses may be developed. As a dynamic cellular process of posttranslational modification, SUMOylation regulates global cellular protein localization, interaction, stability, and enzymatic activity. However, little is known concerning how SUMOylation directly influences virus replication by targeting viral polymerase. Here, we found that EV71 polymerase 3D was SUMOylated during EV71 infection and in vitro Moreover, the SUMOylation sites were determined, and in vitro polymerase assays indicated that mutations at SUMOylation sites could impair polymerase synthesis. Importantly, 3D is ubiquitinated in a SUMOylation-dependent manner that enhances the stability of the viral polymerase. Our findings indicate that the two modifications likely cooperatively enhance virus replication. Our study may offer a new therapeutic strategy against virus replication

Zika virus promotes CCN1 expression via the CaMKIIα-CREB pathway in astrocytes.

Zika virus (ZIKV) infection in the human central nervous system (CNS) causes Guillain-Barre syndrome, cerebellum deformity, and other diseases. Astrocytes are immune response cells in the CNS and an important component of the blood-brain barrier. Consequently, any damage to astrocytes facilitates the spread of ZIKV in the CNS. Connective tissue growth factor/Nephroblastoma overexpressed gene family 1 (CCN1), an important inflammatory factor secreted by astrocytes, is reported to regulate innate immunity and viral infection. However, the mechanism by which astrocyte viral infection affects CCN1 expression remains undefined. In this study, we demonstrate that ZIKV infection up-regulates CCN1 expression in astrocytes, thus promoting intracellular viral replication. Other studies revealed that the cAMP response element (CRE) in the CCN1 promoter is activated by the ZIKV NS3 protein. The cAMP-responsive element-binding protein (CREB), a transacting factor of the CRE, is also activated by NS3 or ZIKV. Furthermore,a specific inhibitor of CREB, i.e. SGC-CBP30, reduced ZIKV-induced CCN1 up-regulation and ZIKV replication. Moreover, co-immunoprecipitation, overexpression, and knockdown studies confirmed that the interaction between NS3 and the regulatory domain of CaMKIIα could activate the CREB pathway, thus resulting in the up-regulation of CCN1 expression and enhancement of virus replication. In conclusion, the findings of our investigations on the NS3-CaMKIIα-CREB-CCN1 pathway provide a foundation for understanding the infection mechanism of ZIKV in the CNS

Effects of atorvastatin and rosuvastatin on blood lipids, platelet aggregation rate and inflammatory factors in patients with cerebral infarction

Purpose: To investigate the effects of atorvastatin and rosuvastatin on blood lipids, platelet aggregation rate (PAR) and inflammatory factors in patients with cerebral infarction.Methods: Patients (n = 120) with cerebral infarction treated in Feng Hua People's Hospital, Jiang Feng Hua, China from January 2014 to October 2016 were randomly divided into control group (clopidogrel combined with atorvastatin, 60 cases) and observation group (clopidogrel combined with rosuvastatin, 60 cases). Blood lipids, PAR, inflammatory factors and carotid atherosclerotic plaque were recorded and compared.Results: Following treatment, total cholesterol (TC), triglycerides (TG) and low  density lipoprotein cholesterol (LDL-C) in the observation group were significantly lower (p < 0.05) than in the control group, while high density lipoprotein cholesterol (HDL-C) was significantly higher (p < 0.05). C-reactive protein (CRP), tumor necrosis factor-α (IL-6) and interleukin-6 (IL-6) were significantly decreased in the two groups after treatment (p < 0.05). Plaque area, intima-media thickness (IMT) and number of plaques in the two groups were significantly lower after treatment than before treatment (p < 0.05). Plaque area, IMT and number of plaques in the observation group were significantly lower than those in the control group (p < 0.05).Conclusion: Atorvastatin and rosuvastatin have no significant effect on the  antiplatelet function of clopidogrel, but rosuvastatin shows better control of blood lipids, carotid atherosclerosis and inflammatory factors.Keywords: Atorvastatin, Rosuvastatin, Cerebral infarction, Blood lipids, Platelet aggregation rate, Inflammatory factor

High-efficiency generation of nanoscale single silicon vacancy defect array in silicon carbide

Color centers in silicon carbide have increasingly attracted attention in recent years owing to their excellent properties such as single photon emission, good photostability, and long spin coherence time even at room temperature. As compared to diamond which is widely used for holding Nitrogen-vacancy centers, SiC has the advantage in terms of large-scale, high-quality and low cost growth, as well as advanced fabrication technique in optoelectronics, leading to the prospects for large scale quantum engineering. In this paper, we report experimental demonstration of the generation of nanoscale $V_{Si}$ single defect array through ion implantation without the need of annealing. $V_{Si}$ defects are generated in pre-determined locations with resolution of tens of nanometers. This can help in integrating $V_{Si}$ defects with the photonic structures which, in turn, can improve the emission and collection efficiency of $V_{Si}$ defects when it is used in spin photonic quantum network. On the other hand, the defects are shallow and they are generated $\sim 40nm$ below the surface which can serve as critical resources in quantum sensing application