ABSTRACT
With alanine as a transient directing group, Pd-catalyzed regioselective alkynylation at the indole C4-position was successfully established in a good yield. The total synthesis of the PAF antagonist demonstrated the synthetic utility of this protocol. The regioselectivity was explicitly proven by the prepared C4-selective palladacycle intermediate in the catalytic process and the DFT calculation of the energy barriers of C4- and C2-site-selective C-H activation of indole.
ABSTRACT
Objective:To study the optimization of defecation treatment in patients with chronic constipation under different positions and angles by "simulation contrast agent".Methods:The clinical data of 78 patients with chronic constipation in Handan Central Hospital from April 2020 to April 2022 were retrospectively analyzed. Among them, 26 patients were examined by 90°conventional defecography position (conventional position group), 26 patients by 60° to 89° defecography position (61° to 89° position group), and 26 patients by 30° to 59° Asian squat defecography position (Asian squat position group). The results of defecography, constipation score and defecography abnormality were compared among the three groups.Results:The encysted rectum, internal rectal intussusception and descending distance of perineum in 61° to 89° position group and Asian squat position group were significantly lower than those in conventional position group: (2.71 ± 0.25) and (2.11 ± 0.66) mm vs. (3.06 ± 0.23) mm, (9.06 ± 1.78) and (8.55 ± 2.81) mm vs. (10.22 ± 1.59) mm, (11.52 ± 2.70) and (10.52 ± 2.93) mm vs. (12.52 ± 3.43) mm, the indexes in Asian squat position group were significantly lower than those in 61° to 89° position group, and there were statistical differences ( P<0.01); the anal right angle and the anal right angle in force discharge state in 61° to 89° position group and Asian squat position group were significantly higher than those in conventional position group: (120.47 ± 3.35)° and (122.44 ± 3.33)° vs. (118.19 ± 3.66)°, (19.99 ± 3.47)° and (20.25 ± 2.69)° vs. (18.77 ± 2.79)°, the indexes in Asian squat position group were significantly higher than those in 61° to 89° position group, and there were statistical differences ( P<0.01); there was no statistical difference in resting anal right angle among the three groups ( P>0.05). The Longo outlet obstructive constipation score, Wexner constipation score and constipation severity score in 61° to 89° position group and Asian squat position group were significantly lower than those in conventional position group: (14.41 ± 2.66) and (12.24 ± 3.49) scores vs. (16.64 ± 3.37) scores, (13.79 ± 2.74) and (12.83 ± 3.08) scores vs. (15.76 ± 3.56) scores, (13.34 ± 2.72) and (12.31 ± 2.52) scores vs. (16.08 ± 3.57) scores, the indexes in Asian squat position group were significantly lower than those in 61° to 89° position group, and there were statistical differences ( P<0.01). The detection rates of abnormal defecography in conventional position group, 61° to 89° position group and Asian squat position group were 96.15% (25/26), 84.62% (22/26) and 69.23% (18/26), and there was statistical difference ( P<0.05); among them, the detection rate of abnormal defecography in Asian squat position group was significantly lower than that in conventional position group, and there was statistical difference ( P<0.05). Conclusions:The defecation function and imaging indexes are optimized in patients with chronic constipation based on the guidance of "simulation contrast agent" adopted the Asian squat position, and their significantly.
ABSTRACT
The global emergence of SARS-CoV-2 variants has led to increasing breakthrough infections in vaccinated populations, calling for an urgent need to develop more effective and broad-spectrum vaccines to combat COVID-19. Here we report the preclinical development of RQ3013, an mRNA vaccine candidate intended to bring broad protection against SARS-CoV-2 variants of concern (VOCs). RQ3013, which contains pseudouridine-modified mRNAs formulated in lipid nanoparticles, encodes the spike(S) protein harboring a combination of mutations responsible for immune evasion of VOCs. Here we characterized the expressed S immunogen and evaluated the immunogenicity, efficacy, and safety of RQ3013 in various animal models. RQ3013 elicited robust immune responses in mice, hamsters, and nonhuman primates (NHP). It can induce high titers of antibodies with broad cross-neutralizing ability against the Wild-type, B.1.1.7, B.1.351, B.1.617.2, and the omicron B.1.1.529 variants. In mice and NHP, two doses of RQ3013 protected the upper and lower respiratory tract against infection by SARS-CoV-2 and its variants. We also proved the safety of RQ3013 in NHP models. Our results provided key support for the evaluation of RQ3013 in clinical trials.
ABSTRACT
Coronavirus disease 2019 (COVID-19), which is triggered by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, continues to threaten global public health. Developing a vaccine that only requires single immunization but provides long-term protection for the prevention and control of COVID-19 is important. Here, we developed an adeno-associated virus (AAV)-based vaccine expressing a stable receptor-binding domain (SRBD) protein. The vaccine requires only a single shot but provides effective neutralizing antibodies (NAbs) over 598 days in rhesus macaques (Macaca mulatta). Importantly, our results showed that the NAbs were kept in high level and long lasting against authentic wild-type SARS-CoV-2, Beta, Delta and Omicron variants using plaque reduction neutralization test. Of note, although we detected pre-existing AAV2/9 antibodies before immunization, the vaccine still induced high and effective NAbs against COVID-19 in rhesus macaques. AAV-SRBD immune serum also efficiently inhibited the binding of ACE2 with RBD in the SARS-CoV-2 B.1.1.7 (Alpha), B.1.351 (Beta), P.1/P.2 (Gamma), B.1.617.2 (Delta), B.1.617.1/3(Kappa), and C.37 (Lambda) variants. Thus, these data suggest that the vaccine has great potential to prevent the spread of SARS-CoV-2.