Lnc-RPS6P3 Inhibits Influenza A Virus Replication and Attenuates the Inhibitory Effect of NS1 on Innate Immune Response.

Host factors play important roles in influenza A virus (IAV) replication. In order to identify novel host factors involved in IAV replication, we compared the differentially expressed genes in A549 cells after IAV infection. We found that lncRNA lnc-RPS6P3 was up-regulated upon viral infection and poly(I:C) and IFN-ß treatment, indicating it was an interferon-stimulated gene. Functional analysis demonstrated that overexpression of lnc-RPS6P3 inhibited IAV replication while knockdown of lnc-RPS6P3 promoted viral infection in A549 cells. Lnc-RPS6P3 inhibited both transcription and replication of IAV. Further study showed that lnc-RPS6P3 interacted with viral NP and interfered with NP self-oligomerization and, consequently, inhibited vRNP activity. In addition, lnc-RPS6P3 interacted with viral NS1 and reduced the interaction of NS1 and RIG-I; it also attenuated the inhibitory effect of NS1 on IFN-ß stimulation. In conclusion, we revealed that lnc-RPS6P3 is an interferon-stimulated gene that inhibits IAV replication and attenuates the inhibitory effect of NS1 on innate immune response.

Ultraflexible, High-Performance Transistors and Logic Circuits on Biocompatible Polylactic Acid (PLA) Substrate.

Wearable and implantable devices have gained significant popularity, playing a crucial role in smart healthcare and human-machine interfaces, which necessitates the development of more complex electronic devices and circuits on biocompatible flexible materials. Polylactic acid (PLA) stands out due to its biodegradability, cost-effectiveness, and low immunogenicity. In this study, we utilize a solution-based spin-coating method to produce high-quality PLA thin films, serving as substrates for the fabrication of thin-film transistors (TFTs) in which the dielectric layer material is silicon dioxide, the channel layer material is IGZO, and the gate, drain, and source material is ITO at low temperatures (<40 °C) through a shadow masking technique. The resulting PLA-TFT devices exhibited remarkable flexibility, biocompatibility, and impressive electrical characteristics, including a charge carrier mobility of 27.81 cm2/(V s), a subthreshold swing of 162.8 mV/decade, and an ON/OFF current ratio of up to 1 × 106, and maintained performance under various deformations. We successfully constructed fundamental logic gate circuits using PLA-TFTs, including AND, OR, and NOT gates, which effectively performed logical functions and demonstrated stability under diverse bending conditions. These research findings provide valuable support for future endeavors in fabricating intricate logic circuits and realizing advanced functionalities on biocompatible flexible materials.

The circRNA circVAMP3 restricts influenza A virus replication by interfering with NP and NS1 proteins.

Circular RNAs (circRNAs) are involved in various biological roles, including viral infection and antiviral immune responses. To identify influenza A virus (IAV) infection-related circRNAs, we compared the circRNA profiles of A549 cells upon IAV infection. We found that circVAMP3 is substantially upregulated after IAV infection or interferon (IFN) stimulation. Furthermore, IAV and IFN-ß induced the expression of QKI-5, which promoted the biogenesis of circVAMP3. Overexpression of circVAMP3 inhibited IAV replication, while circVAMP3 knockdown promoted viral replication, suggesting that circVAMP3 restricts IAV replication. We verified the effect of circVAMP3 on viral infection in mice and found that circVAMP3 restricted IAV replication and pathogenesis in vivo. We also found that circVAMP3 functions as a decoy to the viral proteins nucleoprotein (NP) and nonstructural protein 1 (NS1). Mechanistically, circVAMP3 interfered with viral ribonucleoprotein complex activity by reducing the interaction of NP with polymerase basic 1, polymerase basic 2, or vRNA and restored the activation of IFN-ß by alleviating the inhibitory effect of NS1 to RIG-I or TRIM25. Our study provides new insights into the roles of circRNAs, both in directly inhibiting virus replication and in restoring innate immunity against IAV infection.

Self-assembled short peptides: Recent advances and strategies for potential pharmaceutical applications.

Self-assembled short peptides have intrigued scientists due to the convenience of synthesis, good biocompatibility, low toxicity, inherent biodegradability and fast response to change in the physiological environment. Therefore, it is necessary to present a comprehensive summary of the recent advances in the last decade regarding the construction, route of administration and application of self-assembled short peptides based on the knowledge on their unique and specific ability of self-assembly. Herein, we firstly explored the molecular mechanisms of self-assembly of short peptides, such as non-modified amino acids, as well as Fmoc-modified, N-functionalized, and C-functionalized peptides. Next, cell penetration, fusion, and peptide targeting in peptide-based drug delivery were characterized. Then, the common administration routes and the potential pharmaceutical applications (drug delivery, antibacterial activity, stabilizers, imaging agents, and applications in bioengineering) of peptide drugs were respectively summarized. Last but not least, some general conclusions and future perspectives in the relevant fields were briefly listed. Although with certain challenges, great opportunities are offered by self-assembled short peptides to the fascinating area of drug development.

GABRP promotes CD44s-mediated gemcitabine resistance in pancreatic cancer.

Background: Pancreatic ductal adenocarcinoma (PDAC) has the worst five-year overall survival rate among all cancer types. Acquired chemoresistance is considered one of the main reasons for this dismal prognosis, and the mechanism of chemoresistance is unknown. Methods: We previously identified a subpopulation of chemoresistant CD44high-expressing PDAC cells. Subsequently, we selected the candidate gene, gamma-aminobutyric acid receptor subunit Pi (GABRP), from three Gene Expression Omnibus datasets as the potential CD44 downstream target mediating the gemcitabine resistance. Loss and gain of function such as stable knockdown of CD44 by small hairpin (sh) RNA-mediated silencing technique and overexpression (O/E) of CD44s had been studied for comparing the gemcitabine resistance among CD44high-expressing cells, shCD44 cells, CD44low-expressing cells and O/E CD44s expressing cells. Functional assays including cell viability, colony formation, invasion, quantitative PCR and western blotting techniques were performed to validate the roles of CD44 and GABRP playing in mediating the gemcitabine resistance in pancreatic cancer cells. Results: CD44s depletion significantly reduced gemcitabine resistance in shCD44 single clone cells compared to CD44high-expressing cells. Knockdown of CD44 cells formed less colonies, became less invasive and remarkably decreased the mRNA level of GABRP. While overexpression of CD44s had the opposite effect on gemcitabine resistance, colony formation and invasive property. Of note, long term gemcitabine resistant pancreatic cancer cells detected increased expression of CD44 and GABRP. Clinically, GABRP expression was significantly upregulated in the tissues of patients with pancreatic cancer compared to the normal samples, and the overall survival rate of patients with low GABRP expression was longer. CD44 and GABRP co-expression was positively correlated in 178 pancreatic cancer patients. Conclusion: Our findings suggest that GABRP may serve as a CD44s downstream target to diminish gemcitabine resistance in pancreatic cancer, and both CD44s and GABRP molecules have the potential to become prognostic biomarkers for PDAC patients with gemcitabine resistance.

Inhibitory effect of Buddlejasaponin IVb on porcine epidemic diarrhea virus in vivo and in vitro.

Porcine epidemic diarrhea virus (PEDV) is one of the main pathogens causing severe diarrhea in piglets. Infection of the host induces apoptosis, causing huge economic losses to the pig industry. At present, the preventive and therapeutic effects of commercial vaccines are not satisfactory, and it is necessary to develop new anti-PEDV drugs. In this study, we screened the PEDV-inhibiting drug Buddlejasaponin IVb from the natural product library, and determined the inhibitory effect of Buddlejasaponin IVb on PEDV proliferation in a dose-dependent manner. By exploring the effect of Buddlejasaponin IVb on the life cycle of PEDV, it was found that Buddlejasaponin IVb mainly inhibits the replication and release stages of PEDV, but there is no report at home and abroad. In addition, Buddlejasaponin IVb can inhibit PEDV-activated NF-κB signaling pathway by downregulating PEDV or LPS induced elevation of cytokine levels (IL-6, IL-8, IL-1ß, TNF-α). Finally, we returned to in vivo experiments to explore the antiviral effects of the drug in pigs. The results show that Buddlejasaponin IVb can effectively relieve the clinical symptoms and intestinal damage caused by PEDV infection in pigs. Therefore, this study will provide an important basis for the research on antiviral drugs of PEDV and its members, and at the same time provide guidance for the actual production, which has important application prospects.

RPS4XL encoded by lnc-Rps4l inhibits hypoxia-induced pyroptosis by binding HSC70 glycosylation site.

Pyroptosis is involved in pulmonary hypertension (PH); however, whether this process is regulated by long non-coding RNAs (lncRNAs) is unclear. Some lncRNAs encode peptides; therefore, whether the regulation of pyroptosis in PH depends on lncRNAs themselves or their encoded peptides needs to be explored. We aimed to characterize the role of the peptide RPS4XL encoded by lnc-Rps4l and its regulatory mechanisms during pyroptosis in PH. Transgenic mice overexpression of lnc-Rps4l was established to rescue the inhibition of hypoxia-induced pyroptosis in pulmonary artery smooth muscle cells (PASMCs). An adeno-associated virus 9 construct with a mutation in the open reading frame of lnc-Rps4l was used to verify that it could inhibit hypoxia-induced PASMCs pyroptosis through its encoded peptide RPS4XL. Glutathione S-transferase (GST) pull-down assays revealed that RPS4XL bound to HSC70, and microscale thermophoresis (MST) was performed to determine the HSC70 domain that interacted with RPS4XL. Through glycosylation site mutation, we confirmed that RPS4XL inhibited hypoxia-induced PASMCs pyroptosis by regulating HSC70 glycosylation. Our results showed that RPS4XL inhibits pyroptosis in a PH mouse model and hypoxic PASMCs by regulating HSC70 glycosylation. These results further clarify the important mechanism of vascular remodeling in PH pathology.