Catalytic Asymmetric [4 + 2] Cycloaddition of ortho-Alkenyl Naphthols/Phenols with ortho-Quinone Methides: Highly Stereoselective Synthesis of Chiral 2,3,4-Trisubstituted Chromans.

Chiral phosphoric acid-catalyzed biomimetic asymmetric [4 + 2] cycloaddition of ortho-alkenyl naphthols/phenols and ortho-quinone methides (o-QMs) has been demonstrated to afford various important 2,3,4-trisubstituted chromans in high yields with excellent enantio- and diastereoselectivities (up to 99% yield, 99% ee, >20:1 dr). Notably, this methodology not only enabled access to the trans-cis chiral trisubstituted chromans from 1-alkenyl 2-naphthols but also is compatible with 2-alkenyl 1-naphthols and phenols to deliver trans-trans chiral trisubstituted chromans.

Enantioselective synthesis of chiral α-alkynylated thiazolidones by tandem S-addition/acetalization of alkynyl imines.

A SPINOL-derived chiral phosphoric acid catalyzed asymmetric formal [2 + 3]-annulation of in situ generated alkynyl imines and 1,4-dithiane-2,5-diol has been developed to afford enantiopure α-alkynylated thiazolidones with up to 72% yield and 98.5 : 1.5 er. This tandem annulation involved a tandem S-addition of alkynyl imines/intramolecular acetalization, followed by PDC-mediated oxidation. The α-alkynylated thiazolidones could facilely afford the corresponding chiral α-alkynylated or α-alkenylated cyclic sulfoxides via further elaboration.

Total Synthesis of (±)-Lycojaponicumin D and Lycodoline-Type Lycopodium Alkaloids.

Lycopodium alkaloids with structural diversity and biological significance have been stimulating an increasing interest in the synthetic and medicinal communities, in which inspiration and exploration of their related biogenetic relationship generally constitute one of the major concerns. Driven by the plausible biogenetic entry to lycojaponicumin D as the first member of Lycopodium alkaloids having a structurally unusual C3-C13-linked scaffold, a new connection with lycodoline has been proposed and discovered on the basis of the design of an unprecedented bioinspired tandem fragmentation/Mannich reaction. Initiated by expeditious assembly of bridgehead heterofunctionalization in the [3.3.1] bicyclic system of lycodoline, a novel tandem palladium-mediated oxidative dehydrogenation/hetero-Michael reaction has been developed for the strain-driven formation of the C-heteroatom bond, leading to a new approach to conformationally rigid bridgehead heteroquaternary carbons. The present unified strategy provides a scenario for the divergent total syntheses of nine natural Lycopodium alkaloids and four unnatural C12 epimers, wherein (±)-lycojaponicumin D and six lycodoline-type alkaloids have been synthetically achieved for the first time.

Cinchona Alkaloid Catalyzed Enantioselective [4 + 2] Annulation of Allenic Esters and in Situ Generated ortho-Quinone Methides: Asymmetric Synthesis of Functionalized Chromans.

A novel enantioselective [4 + 2] annulation of the allenoates having a unique positive ortho-effect with in situ generated ortho-quinone methides has been developed under the catalysis of Cinchona alkaloid. This chiral amine-catalyzed reaction provides an alternative route to asymmetric catalytic construction of synthetically interesting, highly functionalized chiral chromans in good to excellent enantioselectivities (up to 97% ee).

Spirocyclopropanation Reaction of para-Quinone Methides with Sulfonium Salts: The Synthesis of Spirocyclopropanyl para-Dienones.

A novel DBU-mediated stereoselective spirocyclopropanation of para-quinone methides with sulfonium salts has been developed on the basis of the mode involving a 1,6-conjugate addition/intramolecular dearomatizing cyclization cascade. This reaction provides a mild and effective method for the assembly of synthetically and structurally interesting spirocyclopropanyl para-dienones. The feasibility for the enantioselective access to such functionalized para-dienones has also been explored by using the axially chiral sulfonium salt. Importantly, the regioselective ring openings of the related spirocyclopropanyl para-dienones have been achieved divergently.

Diastereoselective and Enantioselective Synthesis of Unsymmetric ß,ß-Diaryl-α-Amino Acid Esters via Organocatalytic 1,6-Conjugate Addition of para-Quinone Methides.

A novel strategy based on phase transfer catalysis for the diastereoselective and enantioselective direct assembly of unsymmetric ß,ß-diaryl-α-amino acid esters via 1,6-conjugate addition of para-quinone methides and glycine derivatives is described. This protocol also provides an alternative route to the synthetically interesting functionalized chiral tetrahydroisoquinoline and its analogues.

Highly enantioselective aldol reactions between acetaldehyde and activated acyclic ketones catalyzed by chiral primary amines.

Highly enantioselective cross-aldol reactions between acetaldehyde and activated acyclic ketones are reported for the first time. Various acyclic ketones, such as saturated and unsaturated keto esters, reacted with acetaldehyde in the presence of a chiral primary amine and a Brønsted acid to afford optically enriched tertiary alcohols in good yields and with excellent enantioselectivities. Trifluoromethyl ketones were tolerable under the reaction conditions, thereby affording the trifluoromethyl carbinol in good-to-excellent yields and enantioselectivities. Structural modification of the chiral amines from the same chiral source switched the stereoselectivity of the products. The utility of aldol chemistry was demonstrated in the brief synthesis of functionally enriched δ-lactones. Theoretical calculations on the transition-state structure indicated that the protonated tertiary amine could effectively activate the carbonyl group of a keto ester to promote the addition process through hydrogen-bonding interaction and, simultaneously, provide an appropriate attacking pattern for the approach of the keto ester to the enamine, which is formed from acetaldehyde and the chiral catalyst, on a particular face, resulting in high enantioselectivity.

Combinatory effects of hepatic CD8+ and NK lymphocytes in bile duct injury from biliary atresia.

INTRODUCTION: To our knowledge, elucidating the immune pathogenesis of disease, especially characteristic T-cell and natural killer (NK) cell expansions, has not been performed before now. We investigated the role of T lymphocytes and NK lymphocytes in the destruction of extrahepatic bile ducts of patients with biliary atresia. METHODS: Lymphocytes from the liver and extrahepatic bile duct remnants of patients with biliary atresia were characterized by immunofluorescence staining, fluorescence-activated cell sorter analysis, and real-time reverse-transcriptase PCR. Cholangiocyte lysis assays were performed to confirm cytotoxicity of activated hepatic NK lymphocytes or CD8(+) cells. RESULTS: The inflammatory milieu from portal tracts and/or biliary remnants consisted of greater numbers of Kupffer cells, T lymphocytes, and NK lymphocytes in the patients with biliary atresia as compared with the cholestatic and noncholestatic controls. In patients with biliary atresia, expression of NK or CD8+ costimulatory molecules was upregulated as compared with controls. Hepatic NK lymphocytes or CD8(+) cells from patients with biliary atresia were demonstrated to be cytotoxic to the duct epithelium. DISCUSSION: Specific immune responses from NK and CD8(+) cells were involved in the injury to the duct epithelium and play a significant role in the phenotype of experimental biliary atresia.

Analysis of healthcare-associated infection in patients with pulmonary arterial hypertension associated with congenital heart disease in PICU: Evidence from a tertiary hospital in western China.

Objective: The present study intends to analyze the targeted surveillance and risk factors for healthcare-associated infection (HAI) in patients with pulmonary arterial hypertension associated with congenital heart disease (CHD-PAH) in a Pediatric intensive care unit (PICU), and provide basis for formulating relevant prevention and control measures of HAI. Methods: Children (≤14 years old) who were admitted to the PICU for ≥2 calendar days from January 2018 to December 2021 were included. Targeted surveillance of HAI was described. Results: A total of 7,828 patients in PICU were monitored, and the total hospitalization days of the patients were 36,174. 108 cases of HAI occurred, with a per-case infection rate of 1.38% and a per-thousand day infection rate of 2.99. 1,129 patients with CHD-PAH were included, among which the total hospitalization days were 1,483. In this subpopulation, 38 cases of HAI were diagnosed, with a per-case infection rate of 3.37% and a per-thousand day infection rate of 25.62. The main site of HAI was lower respiratory tract (43.51%), followed by blood infection (34.26%) and surgical site infection (9.26%). 36 strains of pathogenic bacteria were detected from patients with HAI. The top three pathogens with the highest detection rate were Klebsiella pneumoniae (6 episodes, 16.67%), Enterococcus faecium (6 episodes, 16.67%) and Acinetobacter baumannii (4 episodes, 11.11%). The incidence of VAP, CAUTI and CLABSI was 2.78, 0.08 and 1.66 per 1,000 catheter days respectively. Analysis revealed that patients with CHD-PAH were younger and prone to receive surgical corrections. CHD-PAH could significantly increase the length of ICU stay, ventilator days, times of central venous catheterization and central venous catheterization days. The choice of different central venous catheter types differed significantly between the two groups. Conclusion: Patients with CHD-PAH are characterized with excessive central venous catheterization operations, prolonged indwelling time, and more types of catheterization, which are considered to be risk factors for HAI, thus increasing the length of hospital stay. The clinical etiology is mainly G-bacteria, which requires reasonable selection of antibiotics and strict aseptic operation. Limiting unnecessary invasive procedures is helpful for reducing the incidence of postoperative HAI in PICU.

Catalytic Enantioselective Desymmetrization of Prochiral Triacylamines via Pseudopeptidic Guanidine-Guanidinium Catalysis.

Triacylamines with Cs symmetry have been explored in asymmetric organocatalysis, leading to the development of a novel catalytic enantioselective desymmetrization of prochiral triacylamines by methanolysis under the catalysis of chiral pseudopeptidic guanidine-guanidinium salt having a weakly coordinating anion. This organocatalytic methodology provides an effective approach to the synthetically useful chiral imide-esters with a 1,5-dicarbonyl moiety, and its synthetic potential has been manifested in the asymmetric synthesis of two GABA analogue drugs, (R)-Baclofen·HCl and (S)-Pregabalin.

Analysis of biliary epithelial-mesenchymal transition in portal tract fibrogenesis in biliary atresia.

BACKGROUND: The cellular origin of myofibroblast in the liver fibrosis remains unclear. This study was designed to investigate whether biliary epithelial cells (BECs) undergoing epithelial-mesenchymal transition (EMT) might be found in patients with biliary atresia, thereby serving as a source of fibrotic myofibroblasts. METHODS: Liver sections from patients with biliary atresia were evaluated to detect antigen for the BECs marker 4 and cytokeratin-7 (CK-7), proteins (fibroblast-specific protein 1, also known S100A4; the collagen chaperone heat shock protein 47, HSP47) characteristically expressed by cells undergoing EMT, as well as myofibroblasts marker a-smooth muscle actin (a-SMA). RESULTS: Normal bile ducts BECs could express CK-7 and low levels of a-SMA; they did not express S100A4 and HSP47. However, BECs from biliary atresia resulted in increased expression of a-SMA, S100A4, with concurrent transition to a fibroblast-like morphology and decreased expression of AK-7. Furthermore, BECs in biliary atresia were associated with significant bile ductular proliferation and coexpressed both epithelial and mesenchymal markers. CONCLUSIONS: From significant histologic evidence, the BECs forming small- and medium-sized bile ducts undergoing EMT may account for prominent bile ductular proliferation and directly contribute to fibrogenesis in BA.

Usage of 64-detector-row spiral computed tomography volumetry in preoperative volume prediction in living donor liver transplantation in children.

PURPOSE: To investigate the correlation between the graft volume calculated by 64-detector-row spiral computed tomography (CT) and the graft weight measured during the living donor liver transplantation (LDLT) operation, and try to get an equation to help determine the possible weight of graft before operation. METHODS: 23 donors with left lateral lobe LDLT were enrolled to undergo 64-detector-row spiral CT and the imaging data at the hepatic venous phase was used for whole and partial liver volumetric measurement on a dedicated image postprocessing workstation. The resected part of donor liver was weighed during the operation. Statistical analysis with SPSS15.0 was used to analyze the correlation between the estimated liver volume by CT and the actual graft weight. RESULTS: The graft volume calculated preoperatively by CT (293.35 ± 53.43 ml) was significantly larger than measured graft weight during the operation (252.82 ± 50.96 g) (P < 0.05). All corresponding pre- and intraoperative data correlated significantly (R = 0.885) (P < 0.001). Intraoperatively expected weight (W (intraop)) in grams and volume calculated preoperatively by CT (V (preop)) in milliliters can be calculated with the equation W (intraop) (g) = 0.844 × V (preop) (ml) + 5.271. CONCLUSION: Liver volume calculated by 64-detector-row spiral CT preoperatively can predict the actual graft weight, which is very useful in donor selection in LDLT.

Palladium-Catalyzed Asymmetric Direct Intermolecular Allylation of α-Aryl Cyclic Vinylogous Esters: Divergent Synthesis of (+)-Oxomaritidine and (-)-Mesembrine.

We demonstrate that α-aryl cyclic vinylogous esters are competent substrates in the direct intermolecular Pd-catalyzed asymmetric allylic alkylation, enabling a straightforward enantioselective synthesis of 6-allyl-6-aryl-3-ethoxycyclohex-2-en-1-ones, common motifs embedded in numerous structurally diverse natural products. As an initial demonstration of the utility of this protocol, the first catalytic enantioselective total synthesis of (+)-oxomaritidine and an improved five-step catalytic enantioselective synthesis of (-)-mesembrine have been completed divergently.

Palladium-Catalyzed Asymmetric (4 + 2) Annulation of γ-Methylidene-δ-valerolactones with Alkenes: Enantioselective Synthesis of Functionalized Chiral Cyclohexyl Spirooxindoles.

An unprecedented asymmetric catalytic (4 + 2) annulation reaction of aryl-substituted γ-methylidene-δ-valerolactones (GMDVs) with isatin-derived para-quinone methides (p-QMs) has been developed under the catalysis of palladium(0) and (S,S,S)-(-)-Xyl-SKP, offering a new approach for the diastereo- and enantioselective synthesis of chiral cyclohexadienone-fused cyclohexyl spirooxindoles. Significantly, three highly congested contiguous tetrasubstituted carbon atoms embedded in bispirocyclic skeleton, of which two are vicinal quaternary stereogenic centers, are forged in an effective and selective manner (up to 99% yield, up to 95% ee, >20/1 dr). The current reaction represents the first exploration of enantioselective catalytic (4 + 2) annulation forming the six-membered carbocycles in the chemistry of both GMDVs and p-QMs.

Tandem (2 + 2) Annulation/Retro-4π Electrocyclization/Imino-Nazarov Cyclization Reaction of p-Quinone Methides with Ynamides: Expeditious Construction of Functionalized Aminoindenes.

A new tandem annulation of p-quinone methides (p-QMs) with ynamides is described. This cascade reaction features a unique combination of (2 + 2) annulation, retro-4π electrocyclization, and imino-Nazarov cyclization, wherein vinyl p-quinone methides (p-VQMs) as one of the key intermediates have been identified chemically. Significantly, an unusual structural reconstruction of p-QMs involving the cleavage of the C5-C6 bond and the late-stage formation of the C4-C6 bond is involved, leading to a methodology development for the construction of functionalized aminoindenes.

Prognostic value of hedgehog signal component expressions in hepatoblastoma patients.

OBJECTIVE: Activation of hedgehog (Hh) pathway has been implicated in the development of human malignancies. Hh as well as related downstream target genes has been extensively studied in many kinds of malignant tumours for clinical diagnostic or prognostic utilities. This study aimed at investigating whether Hh molecules provides a molecular marker of hepatoblastoma malignancy. METHODS: We obtained tissue sections from 32 patients with hepatoblastoma as well as cholestasis and normal control. Immunohistochemical analysis were performed to determine Hh signal components in human hepatoblastoma. The prognostic significance of single expression of Hh signal components were evaluated using Cox proportional hazards regression models and Kaplan-Meier survival analysis for statistical analysis. RESULTS: Expression of Hh signal components showed an increase in hepatoblastoma compared with cholestasis and normal tissues. There was a positive correlation between Smo or Gli1 expression and tumor clinicopathological features, such as histological type, tumor grade, tumor size and clinical stage. Both Smo or Gli1 protein high expression was significantly associated with poor prognosis by univariate analyses and multivariate analyses. CONCLUSIONS: Abnormal Hh signaling activation plays important roles in the malignant potential of hepatoblastoma. Gli1 expression is an independent prognostic marker.

[Clinical study of 28 patients with adult-to-infant living donor liver transplantation].

OBJECTIVE: To summarize our experience in adult-to-infant living donor liver transplantation (A-ILDLT) and to analyze the efficacy and complications of A-ILDLT. METHODS: The clinical data, surgical strategies and complications of 28 adult donors and infantile recipients who underwent A-ILDLT from April 2006 to December 2009 were retrospectively analyzed. These 28 patients (14 boys and 14 girls) aged from 80 days to 11.5 months with body weights of 3.08 to 10.3 kg at the time of operation . They suffered from biliary atresia with decompensated cirrhosis. The living donors were 15 mothers, 9 fathers, 3 grandma and 1 elder brother with ABO compatible with the infantile recipients. 27 Donor organs were the left lateral lobe grafts (segment II, III) and 1 graft was segment II. All patients were followed up for 5 to 24 months. RESULTS: These grafts were orthotopically transplanted into the infantile recipients. The average length of stay was 9.3 days for the donor group without any complications. Postoperative immunosuppression included prednisone, Cyclosporin and mycophenolate mofetil (MMF). A total of 24 postoperative complications occurred in 20 recipients, including 5 vascular complications, 4 bleeding, 7 pneumonia, 2 bowel obstruction, 4 intestinal perforation and 3 rejection. Three recipients died of hepatic arterial thrombosis (HAT). The perioperative mortality rate of recipients was 10.7% (3/28) and the survival rate was 89.3% in peroperative period. One died of stricture of hepatic vein and 1 of accidental asphyxia during follow-up term. At present, 23 cases are still alive. CONCLUSION: A-ILDLT has become an effective method to infants with end-stage liver disease. The postoperative vascular complication is the predominant cause of death.

P(NMe2)3-Mediated Umpolung Spirocyclopropanation Reaction of p-Quinone Methides: Diastereoselective Synthesis of Spirocyclopropane-Cyclohexadienones.

An unprecedented umpolung spirocyclopropanation reaction of p-quinone methides and α-keto carbonyls is described. Our umpolung strategy based on 1,6-conjugate addition and intramolecular nucleophilic substitution offers a new method for effective access to a series of highly functionalized spirocyclohexadienonyl cyclopropanes having two vicinal quaternary carbons in ≤98% yield and >20:1 dr. Significantly, cyclic and acyclic topological structures of α-keto carbonyls as 1,1-dipole one-carbon synthons have a distinct influence on the stereochemistry of products, showing a reversal of diastereoselectivity in this P(NMe2)3-mediated umpolung spirocyclopropanation.

Palladium-Catalyzed Asymmetric (2+3) Annulation of p-Quinone Methides with Trimethylenemethanes: Enantioselective Synthesis of Functionalized Chiral Spirocyclopentyl p-Dienones.

A novel asymmetric catalytic (2+3) annulation of p-quinone methides with CN-substituted trimethylenemethane is described under palladium catalysis, providing an alternative approach for the enantioselective construction of highly functionalized chiral spirocyclopentyl p-dienones. Driven by the significant improvement in the reactivity and enantioselectivity, a novel type of non-C2-symmetric phosphoramidite ligand from the chirality-matched combination of (S)-BINOL and sterically demanding amine derived from l-hydroxyproline is evolved and explored for the protocol presented here.

[Measurement of fine-structure branching ratios for Rb-He optical collisions].

Experimental ratios of branching in the fine-structure levels of the Rb5P multiplet, as a consequence of an optical collision with He, are reported. The process studied is Rb(5S1/2 )+ He + hrv --> Rb(5P(J)) +He, where the pulsed laser frequency v is tuned in the wings of the Rb resonance transitions. The authors defined the detuning delta to be v-v (D2 )(delta > 0) for laser frequency v highter than that of RbD2 transition and to be v-v (D1)(delta < 0) for v lower than the RbD1 transition. As RbHe molecular states are correlated to the two 5 2P(J) states, there is some likelihood that the molecule will dissociate into 5 2P1/2 or 5P3/2 state. The dissociation results in a nonuniform distribution of atomic Rb5P(J) states. The branching ratios are defined as n1/n2, where n1 and n2 are densities of the 5P1/2 and 5P3/2 states dissociated. To determine experimentally the relative cross section for scattering into the two fine-structure states, the relative time-intergrated intensities of the resulting Rb emission lines, I(5P3/2 --> 5P1/2 )[I(D2)] and I(5P1/2 --> 5P3/2) ) [I(D1)], were measured. The ratios are determined by detunings from about 200 cm(-1) in the blue wing to -180 cm(-1) in the red wing of the Rb5P multiplet. A rate equation analysis of the pressure dependence was yielded. The branching ratios and cross sections for collisional 5P1/2 --> 5P3/2 transition were obtained from the slope and intercept. The blue-wing branching ratios show a detuning-dependent approach to limit of 0. 2. The branching was found to be very large (-40) in the red wing, irrespective of the detuning. Fine structure changing cross section (1.1 +/- 0.3) x 10(-17) cm2 was measured from wing excitation, and the result is consistent with the cross section obtained from resonant excitation of the Rb5P(J) state. The measurements show a strong sensitivity to interatomic potentials and to nonadiabatic effects in dissociation dynamics.