The rapid emergence of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) variants that evade immunity elicited by vaccination has posed a global challenge to the control of the coronavirus disease 2019 (COVID-19) pandemic. Therefore, developing countermeasures that broadly protect against SARS-CoV-2 and related sarbecoviruses is essential. Herein, we have developed a lipid nanoparticle (LNP)-encapsulated mRNA (mRNA-LNP) encoding the full-length Spike (S) glycoprotein of SARS-CoV-2 (termed RG001), which confers complete protection in a non-human primate model. Intramuscular immunization of two doses of RG001 in Rhesus monkey elicited robust neutralizing antibodies and cellular response against SARS-CoV-2 variants, resulting in significantly protected SARS-CoV-2-infected animals from acute lung lesions and complete inhibition of viral replication in all animals immunized with low or high doses of RG001. More importantly, the third dose of RG001 vaccination elicited effective neutralizing antibodies against current epidemic XBB and JN.1 strains and similar cellular response against SARS-CoV-2 Omicron variants (BA.1, XBB.1.16, and JN.1) were observed in immunized mice. All these results together strongly support the great potential of RG001 in preventing the infection of SARS-CoV-2 variants of concern (VOCs).

The first rate-limiting enzyme of the serine synthesis pathway (SSP), phosphoglycerate dehydrogenase (PHGDH), is hyperactive in multiple tumors, which leads to the activation of SSP and promotes tumorigenesis. However, only a few inhibitors of PHGDH have been discovered to date, especially the covalent inhibitors of PHGDH. Here, we identified withangulatin A (WA), a natural small molecule, as a novel covalent inhibitor of PHGDH. Affinity-based protein profiling identified that WA could directly bind to PHGDH and inactivate the enzyme activity of PHGDH. Biolayer interferometry and LC-MS/MS analysis further demonstrated the selective covalent binding of WA to the cysteine 295 residue (Cys295) of PHGDH. With the covalent modification of Cys295, WA blocked the substrate-binding domain (SBD) of PHGDH and exerted an allosteric effect to induce PHGDH inactivation. Further studies revealed that with the inhibition of PHGDH mediated by WA, the glutathione synthesis was decreased and intracellular levels of reactive oxygen species (ROS) were elevated, leading to the inhibition of tumor proliferation. This study indicates WA as a novel PHGDH covalent inhibitor, which identifies Cys295 as a novel allosteric regulatory site of PHGDH and holds great potential in developing anti-tumor agents for targeting PHGDH.

Objective:To investigate the effects of hyperuricemia on the prognosis of IgA nephropathy (IgAN) using propensity score matching (PSM) method.Methods:IgAN patients proven by biopsy were included. PSM was used to match patients. Kaplan-Meier method was used for survival analysis, and Cox regression analysis was used to analyze the effects of hyperuricemia on IgAN prognosis. Primary outcome events were defined as death, or end-stage renal disease (dialysis, transplantation), or a decrease in estimated glomerular filtration rate (eGFR) greater than 40%. Renal outcome was defined as end-stage renal disease (dialysis, transplantation), or a decrease in eGFR greater than 40%.Results:A total of 1 454 IgAN patients were included in this study, including 850 females and 604 males. Uric acid level was (368.26±92.87) μmol/L in the males, and (277.23±92.71) μmol/L in the females. The median follow-up time was 85.00(56.10, 106.33) months. During the follow-up period, a total of 134 patients reached the primary outcome events, including 5 deaths, 24 dialysis patients, 5 kidney transplant patients, and 100 patients with eGFR decreased by more than 40%. After 1∶1 matching, 131 males and 159 females in the hyperuricemia group were successfully matched with 131 males and 159 females in the normal uric acid group, and there was no significant statistical difference in each parameter in baseline between the hyperuricemia group and normal uric acid group after matching. Kaplan-Meier survival analysis showed that either before or after matching, the incidence of primary outcome events in male or female patients with hyperuricemia was higher than those with normal uric acid, but there was no statistically significant difference in incidence of primary outcome events between female hyperuricemia group and female normal uric acid group after matching (Log-rank test, χ2=3.586, P=0.058). Cox proportional hazard regression model showed that, in the pre-match fully adjusted model, the hazard ratio ( HR) of entering primary outcome events was 2.29-fold (95% CI 1.27-4.11, P=0.006) for men with hyperuricemia and 1.85-fold (95% CI 1.01-3.37, P=0.045) for women with hyperuricemia compared with those with normal uric acid. In the post-match fully adjusted model, the HR of entering primary outcome events was 2.41-fold (95% CI 1.18-4.93, P=0.016) for men with hyperuricemia and 1.83-fold (95% CI 0.91-3.67, P=0.091) for women with hyperuricemia compared with those with normal uric acid. In the pre-match fully adjusted model, the HR of entering renal outcome events was 2.68-fold (95% CI 1.47-4.88, P=0.001) for men with hyperuricemia and 1.81-fold (95% CI 0.99-3.33, P=0.056) for women with hyperuricemia compared with those with normal uric acid. In the post-match fully adjusted model, the HR of entering renal outcome events was 2.89-fold (95% CI 1.36-6.15, P=0.006) for men with hyperuricemia and 1.81-fold (95% CI 0.88-3.72, P=0.106) for women with hyperuricemia compared with those with normal uric acid. Conclusion:Hyperuricemia may be associated with IgAN progression, and it has a more significant effect on male IgAN patients.

Severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) has become one major threat to human population health. The RNA-dependent RNA polymerase (RdRp) presents an ideal target of antivirals, whereas nucleoside analogs inhibitor is hindered by the proofreading activity of coronavirus. Herein, we report that corilagin (RAI-S-37) as a non-nucleoside inhibitor of SARS-CoV-2 RdRp, binds directly to RdRp, effectively inhibits the polymerase activity in both cell-free and cell-based assays, fully resists the proofreading activity and potently inhibits SARS-CoV-2 infection with a low 50% effective concentration (EC

Objective To explore the predictive value of dynamic serum phosphorus levels in the evaluation of prognosis in patients with sepsis. Methods A retrospective study was conducted. The septic patients admitted to intensive care unit (ICU) of the Second People's Hospital of Changzhou from January 2016 to June 2017 were enrolled, who were ≥18 years old and whose length of ICU stay > 72 hours. These patients were divided into survival group and death group according to 28-day outcome. The general information, the acute physiology and chronic health evaluation Ⅱ(APACHE Ⅱ) score within 24 hours of ICU admission, the serum phosphorus at 1, 3, 5, 7 days after admission were collected. Receiver operating characteristic curve (ROC) was plotted according to the dynamic serum phosphorus levels and APACHE Ⅱ score for evaluating the predictive value of 28-day prognosis. Kaplan-Meier survival curve was used to analyze the 28-day cumulative survival rate between two groups of patients, who were divided according to the corresponding time of the serum phosphorus cut-off value. Results ① Eighty-five patients with sepsis were enrolled, among whom 25 cases were in the death group and the mortality was 29.4%. APACHE Ⅱ score in the death group was significantly higher than that in the survival group (22.28±3.98 vs. 16.05±5.44, P < 0.01), the rate of using vasoactive drugs was significantly higher than that in the survival group [64.0% (16/25) vs. 31.7% (19/60), P < 0.01], but there was no significant difference in the length of invasive mechanical ventilation and ICU stay between two groups.② The level of serum phosphorus was increased in survival group along with time of the treatment, and the death group showed a downward trend. The levels of serum phosphorus at 3, 5, 7 days after admission to ICU in death group were significantly lower than those in survival group (mmol/L: 0.90±0.24 vs. 1.05±0.19 at 3 days, 0.96±0.16 vs. 1.11±0.17 at 5 days, 0.83±0.19 vs. 1.21±0.14 at 7 days, all P < 0.01).③ROC curve analysis showed that APACHE Ⅱ score and serum phosphorus level on the 7th day could significantly predict 28-day mortality in patients with sepsis, and the areas under ROC curve (AUC) of them were 0.813 and 0.945 respectively (both P < 0.01). The AUC of serum phosphorus level on the 3rd day and 5th day were 0.692 and 0.745 respectively (both P < 0.01). Based on serum phosphorus cut-off value 1.01 mmol/L on the 7th day to evaluate the predictive value of 28-day mortality, the sensitivity was 91.7%, the specificity was 84.0%, the positive and negative likelihood ratios were 5.73 and 0.10 respectively. ④ Kaplan-Meier survival analysis showed that the 28-day survival rate was significantly higher and the length of survival was significantly longer if the serum phosphorus were higher than the cut-off value at different time points of ICU admission. The 28-day survival rate was significantly higher and the length of survival was significantly longer in the patients with serum phosphorus > 1.01 mmol/L than those serum phosphorus ≤ 1.01 mmol/L on the 7th day [28-day survival rate: 93.2% (55/59) vs. 22.7% (5/22), χ2= 49.697, P = 0.000; survival period (days): 27.1±3.6 vs. 19.8±7.8, t = 4.768, P =0.000]. Conclusion The continuous decline of serum phosphorus indicates poor prognosis, and the serum phosphorus level on the 7th day is one of the most important indicator to evaluate the prognosis of patients with sepsis.

Adult ; Brain ; drug effects ; metabolism ; Female ; Hallucinogens ; adverse effects ; Humans ; Magnetic Resonance Imaging ; Motion Perception ; drug effects ; N-Methyl-3,4-methylenedioxyamphetamine ; adverse effects