The twenty-first century has already recorded more than ten major epidemics or pandemics of viral disease, including the devastating COVID-19. Novel effective antivirals with broad-spectrum coverage are urgently needed. Herein, we reported a novel broad-spectrum antiviral compound PAC5. Oral administration of PAC5 eliminated HBV cccDNA and reduced the large antigen load in distinct mouse models of HBV infection. Strikingly, oral administration of PAC5 in a hamster model of SARS-CoV-2 omicron (BA.1) infection significantly decreases viral loads and attenuates lung inflammation. Mechanistically, PAC5 binds to a pocket near Asp49 in the RNA recognition motif of hnRNPA2B1. PAC5-bound hnRNPA2B1 is extensively activated and translocated to the cytoplasm where it initiates the TBK1-IRF3 pathway, leading to the production of type I IFNs with antiviral activity. Our results indicate that PAC5 is a novel small-molecule agonist of hnRNPA2B1, which may have a role in dealing with emerging infectious diseases now and in the future.

Omega-3 polyunsaturated fatty acids (n-3 PUFAs) exert a negative effect on IL-6 production in several liver disorders, including cirrhosis, acute liver failure and fatty liver disease. However, its effect on the production of IL-11, another important IL-6 family cytokine, remains unclear. IL-11 was found to be significantly elevated in acetaminophen (APAP)-induced liver damage. The aim of the present study was to investigate whether and how n-3 PUFAs modulate IL-11 production during APAP-induced liver injury. For that purpose, wild-type (WT) and fat-1 transgenic mice were intraperitoneally injected with APAP to induce liver injury. Serum was collected for ELISA and alanine aminotransferase assay. The hepatocytes of APAP-injected mice were isolated for reverse transcription-quantitative PCR and western blot analyses. For the in vitro study, primary hepatocytes isolated from WT or fat-1 mice were stimulated with APAP. The results revealed that both endogenous and exogenous n-3 PUFAs significantly aggravated APAP-induced liver damage via the downregulation of STAT3 signaling. Notably, n-3 PUFAs inhibited IL-11 expression, but not IL-6 expression in hepatocytes during the APAP challenge. Furthermore, it was demonstrated that limited phosphorylation of ERK1/2 and Fos-like-1 (Fra-1) expression are responsible for the n-3 PUFA-mediated inhibitory effect on IL-11 production in APAP-treated hepatocytes. It was concluded that n-3 PUFAs inhibit IL-11 production and further STAT3 activation in hepatocytes during APAP-induced liver injury. Therefore, ERK1/2-mediated Fra-1 expression is responsible for the effect of n-3 PUFAs on IL-11 expression.

No abstract

No abstract

Existing research on the vowel system of Singapore English has been limited to acoustic examination and analyses only. The present study thus aims to supplement this area of research by providing articulatory descriptions of the Singapore English vowels, specifically looking at lingual and laryngeal articulation. This is achieved by visualising and recording the tongue and larynx during natural, running speech (a picture description task), through the combined use of lingual and laryngeal ultrasound imaging. With the articulatory data collected, we sought to address a few main questions: (1) What the extent of merger in the long-short and /e/-/ae/ vowel pairs in Singapore English is, both in terms of acoustics and articulation; (2) How advanced /u/-fronting is in Singapore English, if at all; and (3) Whether larynx height varies systematically as a function of vowel quality-even in naturalistic speech. Data analysis revealed that the extent of acoustic merger in the vowel pairs was not as advanced as indicated in previous studies, and there appears to be some differentiation through lingual (and to some extent, laryngeal) articulation in these vowel pairs. We also found that /u/ is produced with a relatively central position in Singapore English, rather than being fully 'back' as traditionally expected. Lastly, the ranking of vowels according to vertical larynx position is surprisingly consistent with past findings despite the nature of our data, and we posit that laryngeal articulation may be actively employed in order to augment the acoustic difference between /e/ and /ae/ in Singapore English.