Search

Human respiratory syncytial virus (RSV) is a leading cause of lower respiratory tract infection worldwide. Until now, there are no licenced vaccines or effective antiviral drugs against RSV infections. In our previous work, we found 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives (4-49 C and 1-HB-63) being a novel inhibitor against RSV in vitro. Here, we explored the underlying mechanism of 2-((1H-indol-3-yl)thio/sulfinyl)-N-pheny acetamide derivatives to inhibit RSV replication in vitro and disclosed that 4–49 C worked as the inhibitor of membrane fusion and 1-HB-63 functioned at the stage of RSV genome replication/transcription. Yet, both of them could not inhibit RSV infection of BALB/c mice by using RSV-Luc, in vivo imaging and RT-qPCR analyses, for which it may be due to the fast metabolism in vivo. Our work suggests that further structural modification and optimisation of 2-((1H-indol-3-yl) thio/sulfinyl)-N-pheny acetamide derivative are needed to obtain drug candidates with effective anti-RSV activities in vivo.

Herpes zoster (HZ) is a disease caused by the reactivation of latent varicella-zoster virus (VZV). The subunit vaccine, Shingrix®, and live attenuated vaccine, Zostavax®, could be used as an HZ vaccine that prevents HZ from being developed due to the reactivation of latent VZV in the sensory ganglia due to aging, stress or immunosuppression. In this study, the recombinant adenoviruses rChAd63/gE expressing glycoprotein E (gE) of VZV based on chimpanzee adenovirus serotype 63 (ChAd63) were constructed and investigated for the immunogenicity of different immune pathways in C57BL/6 mice. The results showed similar CD4+ T and CD8+ T cell responses to Shingrix® were induced in mice vaccinated using rChAd63/gE via different immune pathways. This study elucidates that recombinant adenoviruses expressing VZV gE could be appropriate for further development as a new HZ vaccine candidate via different immune pathways.

Abstract Background Excess cadmium (Cd) intake poses a general risk to health and to the kidneys in particular. Among indices of renal dysfunction under Cd burden measures are the urinary N-acetyl-β-D-glucosidase (UNAG) and urinary β2-microglobulin (Uβ2-MG) enzymes. However, the end-pointed values and the Cd burden threshold remain controversial because the scopes fluctuate widely. Methods To ascertain the clinical benchmark dose of urinary Cd (UCd) burden for renal dysfunction, 1595 residents near a Cd site were surveyed. Urine was sampled and assayed. A benchmark dose low (BMDL) was obtained by fitting UCd levels and index levels. Results We found that over 50% of the subjects were suffering from Cd exposure as their UCd levels far exceeded the national standard threshold of 5.000 μg/g creatinine (cr). Further analysis indicated that Uβ2-MG was more sensitive than UNAG for renal dysfunction. The BMDL for UCd was estimated as 3.486 U/g cr (male, where U is unit of enzyme) and 2.998 U/g cr (female) for UNAG. The BMDL for Uβ2-MG, which is released into urine from glomerulus after Cd exposure, was found to be 2.506 μg/g cr (male, where μg is the unit of microglobulin) and 2.236 μg/g cr (female). Conclusions Uβ2-MG is recommended as the sensitivity index for renal dysfunction, with 2.2 μg/g cr as the threshold for clinical diagnosis. Our findings suggest that Uβ2-MG is the better biomarker for exposure to Cd.

It has been argued that vaccine-breakthrough infections of SARS-CoV-2 would likely accelerate the emergence of novel variants with immune evasion. This study explored the evolutionary patterns of the Delta variant in countries/regions with relatively high and low vaccine coverage based on large-scale sequences. Our results showed that (i) the sequences were grouped into two clusters (L and R); the R cluster was dominant, its proportion increased over time and was higher in the high-vaccine-coverage areas; (ii) genetic diversities in the countries/regions with low vaccine coverage were higher than those in the ones with high vaccine coverage; (iii) unique mutations and co-mutations were detected in different countries/regions; in particular, common co-mutations were exhibited in highly occurring frequencies in the areas with high vaccine coverage and presented in increasing frequencies over time in the areas with low vaccine coverage; (iv) five sites on the S protein were under strong positive selection in different countries/regions, with three in non-C to U sites (I95T, G142D and T950N), and the occurring frequencies of I95T in high vaccine coverage areas were higher, while G142D and T950N were potentially immune-pressure-selected sites; and (v) mutation at the N6-methyladenosine site 4 on ORF7a (C27527T, P45L) was detected and might be caused by immune pressure. Our study suggested that certain variation differences existed between countries/regions with high and low vaccine coverage, but they were not likely caused by host immune pressure. We inferred that no extra immune pressures on SARS-CoV-2 were generated with high vaccine coverage, and we suggest promoting and strengthening the uptake of the COVID-19 vaccine worldwide, especially in less developed areas.

Extracellular plaque deposits of ß-amyloid peptide (Aß) are one of the main pathological features of Alzheimer's disease (AD). The aggregation of Aß42 species, especially Aß42 oligomers, is still an active research field in AD pathogenesis. Secretory clusterin protein (sCLU), an extracellular chaperone, plays an important role in AD pathogenesis. Although sCLU interacts directly with Aß42 in vitro and in vivo, the mechanism is not clear. In this paper, His-tagged sCLU (sCLU-His) was cloned, expressed and purified, and we applied florescence resonance energy transfer-fluorescence correlation spectroscopy (FRET-FCS) to investigate the direct interaction of sCLU-His and Aß42 at the single-molecule fluorescence level in vitro. Here, we chose four different fluorescently labeled Aß42 oligomers to form two different groups of aggregation models, easy or difficult to aggregate. The results showed that sCLU-His could form complexes with both aggregation models, and sCLU-His inhibited the aggregation of Aß42/RB ~ Aß42/Atto647 (easy to aggregate model). The complexes were produced as the Aß42/Label adhered to the sCLU-His, which is similar to a "strawberry model," as strawberry seeds are dotted on the outer surface of strawberries. This work provided additional insight into the interaction mechanism of sCLU and Aß42. [ABSTRACT FROM AUTHOR]