Enantioselective construction of spiro-tetrahydroquinoline scaffolds through asymmetric catalytic cascade reactions.

An efficient and concise strategy has been successfully developed for merging spiro-tetrahydroquinoline with spiro-benzofuranone into a single new skeleton through asymmetric catalytic cascade reactions catalyzed by quinine-derived chiral bifunctional squaramide organocatalysts. In this approach, differently substituted spiro-tetrahydroquinoline derivatives were smoothly obtained with high yields, and excellent diastereoselectivities and enantioselectivities (up to 99% yield, up to >20 : 1 dr, up to >99% ee, 40 examples) under mild reaction conditions.

Safety and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older: two single-center, randomised, double-blind, placebo-controlled, phase 1 and phase 2 trials.

COVID-19 vaccines from multiple manufacturers are needed to cope with the problem of insufficient supply. We did two single-center, randomised, double-blind, placebo-controlled phase 1 and phase 2 trials to assess the safety, tolerability and immunogenicity of a recombinant COVID-19 vaccine (Sf9 cells) in healthy population aged 18 years or older in China. Eligible participants were enrolled, the ratio of candidate vaccine and placebo within each dose group was 3:1 (phase 1) or 5:1 (phase 2). From August 28, 2020, 168 participants were sequentially enrolled and randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 28 days or 0, 14, 28 days in phase 1 trial. From November 18, 2020, 960 participants were randomly assigned to receive the low dose vaccine, high dose vaccine or placebo with the schedule of 0, 21 days or 0, 14, 28 days in phase 2 trial. The most common solicited injection site adverse reaction within 7 days in both trials was pain. The most common solicited systematic adverse reactions within 7 days were fatigue, cough, sore throat, fever and headache. ELISA antibodies and neutralising antibodies increased at 14 days, and peaked at 28 days (phase 1) or 30 days (phase 2) after the last dose vaccination. The GMTs of neutralising antibody against live SARS-CoV-2 at 28 days or 30 days after the last dose vaccination were highest in the adult high dose group (0, 14, 28 days), with 102.9 (95% CI 61.9-171.2) and 102.6 (95% CI 75.2-140.1) in phase 1 and phase 2 trials, respectively. Specific T-cell response peaked at 14 days after the last dose vaccination in phase 1 trial. This vaccine is safe, and induced significant immune responses after three doses of vaccination.

Enantioselective Construction of Polycyclic Indazole Skeletons Bearing Five Consecutive Chiral Centers through an Asymmetric Triple-Reaction Sequence.

A novel approach for the asymmetric construction of polycyclic indazole skeletons via enamine-imine activation and PCET activation was developed by merging organocatalysis with photocatalysis through an asymmetric triple-reaction sequence. In this process, five C-X bonds and five consecutive chiral centers were efficiently constructed. Differently substituted polycyclic indazole deriatives were successfully constructed with satisfactory results under mild conditions.

One-Pot Enantioselective Construction of Polycyclic Tetrahydroquinoline Scaffolds through Asymmetric Organo/Photoredox Catalysis via Triple-Reaction Sequence.

A novel one-pot triple-reaction strategy for the asymmetric construction of polycyclic skeletons with multiple consecutive chiral centers through aza-Michael/Michael/Wittig/ketyl radical addition/esterification processes is reported. A wide range of polycyclic tetrahydroquinoline derivatives were smoothly obtained from easily available starting materials with good results (up to 80% yield, >20:1 dr, >99% ee) under mild conditions. In this transformation, five chemical bonds and five consecutive chiral centers were successively formed.

Pathological Analysis and Endoscopic Characteristics of Colorectal Laterally Spreading Tumors.

OBJECTIVE: This study aims to analyze the endoscopic and pathological characteristics of colorectal laterally spreading tumors (LSTs) to assist malignant risk stratification to inform selection of the appropriate treatment strategy. METHODS: Patients with colorectal LST were selected as retrospective study objects. Characteristics, including endoscopic findings and the most common site of LSTs of different diameters and histological types, were analyzed. The risk factors for malignancy in colorectal LST were explored by multivariate logistic regression analysis. RESULTS: LSTs with diameters of ≥20 mm were found mainly in the rectum and mainly with granular-mixed (G-M) morphology (36% and 44.6%, respectively; p < 0.05), while LSTs with diameters of <20 mm were found mainly in the ascending colon and mainly with granular-homogenous (G-H) morphology (40.9% and 46.2%, respectively; p < 0.05). Adenoma was the main histological type in patients with tumors of all diameters. However, the cancerization rate of LSTs was 31% in patients with tumor diameter ≥20 mm, while there was no invasive cancer in patients with tumor diameter < 20 mm. In the low-grade dysphasia (adenoma) group, most of the lesions were located in the ascending colon and most had the morphology LST-G-H (35.8% and 39.2%, respectively; p < 0.05). In the cancerization group, most of the lesions were located in the rectum, with the morphology LST-G-M (51.6% and 67.2%, respectively; p < 0.05), and the diameter was larger than that of the adenoma group (33.84 ± 17.99 mm vs 21.68 ± 8.99 mm). CONCLUSION: The rectum was the most common site for an LST with a diameter ≥20 mm and cancerization, of which the morphology was mainly LST-G-M (endoscopic submucosal dissection is the preferred treatment for this type of LST). LST malignancy was found to be correlated with lesion diameter, location, and morphological appearance.

Microscopic Manipulation of Ferroelectric Domains in SnSe Monolayers at Room Temperature.

Two-dimensional (2D) van der Waals ferroelectrics provide an unprecedented architectural freedom for the creation of artificial multiferroics and nonvolatile electronic devices based on vertical and coplanar heterojunctions of 2D ferroic materials. Nevertheless, controlled microscopic manipulation of ferroelectric domains is still rare in monolayer-thick 2D ferroelectrics with in-plane polarization. Here we report the discovery of robust ferroelectricity with a critical temperature close to 400 K in SnSe monolayer plates grown on graphene and the demonstration of controlled room-temperature ferroelectric domain manipulation by applying appropriate bias voltage pulses to the tip of a scanning tunneling microscope (STM). This study shows that STM is a powerful tool for detecting and manipulating the microscopic domain structures in 2D ferroelectric monolayers, which are difficult for conventional approaches such as piezoresponse force microscopy, thus facilitating the hunt for other 2D ferroelectric monolayers with in-plane polarization with important technological applications.

Asymmetric Organocatalytic [4 + 1] Annulations Involving a Polarity Reversal Process: A Tandem Catalytic Approach to Highly Functionalized Spiropyrazolone Derivatives.

A tandem catalytic strategy for the asymmetric synthesis of spirocyclopentanone pyrazolones bearing three contiguous stereocenters and two quaternary carbons with good stereoselectivities has been developed. This strategy, using pyrazolones as efficient C1 synthons and involving a polarity reversal process, not only overcame the energy barrier of the dearomatization process but also avoided nucleophilic addition of the hydroxy group in the enol form tautomer. Futhermore, spirocyclopentanones could be transformed into spirocyclohexamide pyrazolone with the Lawesson reagent.

Participation of ß-Ketothioamides in N-Heterocyclic Carbene-Catalyzed [3 + 3] Spiroannulation: Asymmetric Synthesis of Functionalized Spiro-piperidinone Derivatives.

An N-heterocyclic carbene-catalyzed asymmetric [3 + 3] spiroannulation of ß-ketothioamide was successfully developed. ß-Ketothioamides exhibit an unusual reactivity to undergo a previously challenging lactamization reaction, and the desired spiro-piperidinone derivatives containing two vicinal stereogenic centers were synthesized in good to high yields with high stereoselectivities, whose structure can be converted to the corresponding imide and δ-lactam derivatives smoothly.

Role and regulation of growth plate vascularization during coupling with osteogenesis in tibial dyschondroplasia of chickens.

Tibial dyschondroplasia (TD) is the most-prevalent leg disorder in fast-growing chickens; it is intractable and characterized by abnormal endochondral bone formation of proximal tibial growth-plates (TGPs). Previous studies have shown that bone is a highly vascularized tissue dependent on the coordinated coupling between angiogenesis and osteogenesis, but the underlying mechanisms of bone formation and bone remodeling are poorly defined in TD chickens. Here, we observed that inhibition of vasculogenesis and angiogenesis remarkably impaired vascular invasion in the hypertrophic chondrocyte zone of the TGPs, resulting in the massive death of chondrocytes due to a shortage of blood vessels and nutrients. Moreover, the balance of the OPG (osteoprotegerin)/RANKL (receptor activator of nuclear factor-kB ligand) system is also severely disrupted during the osteogenesis process while coupling with angiogenesis, both of which eventually lead to abnormal endochondral bone formation in TD chickens. Thus, the process of vascular formation in endochondral bone appears to initiate the pathological changes in TD, and improvement of this process during coupling with osteogenesis may be a potential therapeutic approach to treat this intractable disease.

Quaternary Carbon Center Forming Formal [3 + 3] Cycloaddition Reaction via Bifunctional Catalysis: Asymmetric Synthesis of Spirocyclohexene Pyrazolones.

A variety of spirocyclohexene pyrazolones were synthesized in good yields with excellent stereoselectivities through an asymmetric, intermolecular, quaternary carbon center forming [3 + 3] cycloaddition reaction catalyzed by a bifunctional catalyst. The vinylogous pyrazolones used as binucleophilic synthons in this reaction exhibited superior ability for constructing pyrazolone related spirocyclic scaffolds.