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Chronic airway inflammation mediated by CD8+ T lymphocytes contributes to the pathogenesis of Chronic obstructive pulmonary disease (COPD). Deciphering the fingerprint of the chronic inflammation orchestrated by CD8+ T cells may allow the development of novel approaches to COPD management. Here, the expression of IL-27 and IFN-γ+ CD8+ Tc1 cells were evaluated in patients with COPD and in cigarette smoke-exposed mice. The production of IL-27 by marrow-derived dendritic cells (mDCs) in response to cigarette smoke extract (CSE) was assessed. The role of IL-27 in IFN-γ+ CD8+ Tc1 cells was explored. We demonstrated that elevated IL-27 was accompanied by an exaggerated IFN-γ+ CD8+ Tc1 response in a smoking mouse model of emphysema. We noted that lung dendritic cells were one of the main sources of IL-27 during chronic cigarette smoke exposure. Moreover, CSE directly induced the production of IL-27 by mDCs in vitro. IL-27 negatively regulated the differentiation of IFN-γ+ CD8+ Tc1 cells isolated from cigarette smoke-exposed mice in a STAT1- and STAT3-independent manner. Systemic administration of recombinant IL-27 attenuated IFN-γ+ CD8+ Tc1 response in the late phase of cigarette smoke exposure. Our results uncovered that IL-27 negatively regulates IFN-γ+ CD8+ Tc1 response in the late stage of chronic cigarette smoke exposure, which may provide a new strategy for the anti-inflammatory treatment of smoking-related COPD/emphysema.

Rhabdomyosarcoma (RMS) with regional lymph node involvement has a high rate of distant metastases. Lung is the most common site, accounting for 70% of all metastases. The differential diagnosis of lung lesions due to an infectious aetiology versus metastases is usually evaluated by computed tomography (CT) or magnetic resonance imaging. However, it is rare for patients of RMS to present with infectious nodules or masses in the lung during follow-up. More importantly, infections can mimic the imaging characteristics of metastatic RMS in CT. We report two such cases where children diagnosed with head and neck embryonal RMS with lymph node metastasis, presented with pulmonary masses 0.5 and 4 years after end of treatment, without the typical signs and symptoms suggestive of an infection. Chest CT suggested a provisional diagnosis of metastases and biopsies confirmed infectious aetiology (Mycobacterium tuberculosis, Cryptococcus).

Acinetobacter baumannii is currently posing a serious threat to global health. Lipopolysaccharide (LPS) is a potent virulence factor of pathogenic Gram-negative bacteria. To explore the antigenic properties of A. baumannii LPS, four Kdo-containing inner core glycans from A. baumannii strain ATCC 17904 were synthesized. A flexible and divergent method based on the use of the orthogonally substituted α-Kdo-(2→5)-Kdo disaccharides was developed. Selective removal of different protecting groups in these key precursors and elongation of sugar chain via α-stereocontrolled coupling with 5,7-O-di-tert-butylsilylene or 5-O-benzoyl protected Kdo thioglycosides and 2-azido-2-deoxyglucosyl thioglycoside allowed efficient assembly of the target molecules. Glycan microarray analysis of sera from infected patients revealed that the 4,5-branched Kdo trimer was a potential antigenic epitope, which is attractive for further immunological research to develop carbohydrate vaccines against A. baumannii.

Azulene is a non-benzenoid aromatic building block with unique chemical structure and physicochemical properties. By using the "bottom-up" synthetic strategy, we synthesized three azulene-embedded [n]helicenes ([n]AzHs, n=5, 6 and 7), in which one terminal azulene subunit was fused with n-2 benzene rings. P- and M-enantiomers were observed in the packing diagrams of [5]-, and [6]AzHs. However, P- and M-[7]AzHs could be isolated by recrystallization of the racemic mixture. These [n]AzHs were endowed with new properties through the azulene moiety such as low-lying first electric state (S

Metabolite‐protein interactions (MPIs) play key roles in cancer metabolism. However, our current knowledge about MPIs in cancers remains limited due to the complexity of cancer cells. Herein, the authors construct an integrative MPI network and propose a MPI network based hepatocellular carcinoma (HCC) subtyping and mechanism exploration workflow. Based on the expressions of hub proteins on the MPI network, two prognosis‐distinctive HCC subtypes are identified. Meanwhile, multiple interdependent features of the poor prognostic subtype are observed, including hypoxia, DNA hypermethylation of metabolic pathways, fatty acid accumulation, immune pathway up‐regulation, and exhausted T‐cell infiltration. Notably, the immune pathway up‐regulation is probably induced by accumulated unsaturated fatty acids which are predicted to interact with multiple immune regulators like SRC and TGFB1. Moreover, based on tumor microenvironment compositions, the poor prognostic subtype is further divided into two sub‐populations showing remarkable differences in metabolism. The subtyping shows a strong consistency across multiple HCC cohorts including early‐stage HCC. Overall, the authors redefine robust HCC prognosis subtypes and identify potential MPIs linking metabolism to immune regulations, thus promoting understanding and clinical applications about HCC metabolism heterogeneity., The authors construct an integrative metabolite‐protein interaction (MPI) network and develop a MPI prediction model. The MPI network helps redefine robust hepatocellular carcinoma prognostic subtypes. The subtypes show remarkable differences in hypoxia, DNA methylation of metabolic enzymes, immune pathways, fatty acid accumulation as well as tumor microenvironment. Meanwhile, unsaturated fatty acids are potential links between the metabolism and immune regulations.

Importance: Retinoblastoma (Rb) is the most common primary malignant intraocular cancer in children. Systemic chemotherapy combined with local therapy is safe and effective for intraocular Rb. Objective: To summarize the short-term outcomes of patients with Rb to provide evidence for optimizing treatment protocols and improving therapeutic safety and efficacy. Methods: The clinical data of 356 patients (486 eyes) with intraocular Rb admitted to our center from December 2009 to April 2017 were retrospectively analyzed. The measures included drug toxicity, eye-preservation rate, and survival rate, with an emphasis on safety and short-term efficacy. The date of last follow-up was 30 November, 2017. Results: The patients comprised 226 unilateral Rb and 130 bilateral Rb. Enucleation before chemotherapy was performed in 72 patients. Among the 174 patients with unilateral Rb, enucleation after chemotherapy was performed in 80 patients (46.0%), and the eye was not enucleated in 89 (51.1%); 68 eyes were preserved (68/114, 59.6%) in Group D and 20 eyes (20/59, 33.8%) in Group E. Among the 220 eyes in patients with bilateral Rb, enucleation after chemotherapy was performed for 35 eyes; the eye-preservation rate was 91.7% in Group C, 79.1% in Group D, and 52.1% in Group E. All patients developed grade II to IV myelosuppression after chemotherapy, among whom 18 patients (5%) requiring transfusion. Fourteen patients (3.9%) died of intracranial metastasis following self-elected discontinuation of treatment (n = 7). Patients were followed up for a median of 47 (range, 1–96) months. The expected 5-year overall survival rate was 95.3% (96.7% for unilateral Rb and 92.9% for bilateral Rb, P = 0.074). Interpretation: The VEC (vincristine, etoposide, and carboplatin) regimen with local treatment was safe for intraocular Rb. Intracranial metastasis remains the most common cause of Rb-related death. Key words: Chemotherapy; Enucleation; Intraocular retinoblastoma; Local therapy

An infection-age virus dynamics model for human immunodeficiency virus (or hepatitis B virus) infections with saturation effects of infection rate and immune response is investigated in this paper. It is shown that the global dynamics of the model is completely determined by two critical values R0, the basic reproductive number for viral infection, and R1, the viral reproductive number at the immune-free infection steady state (R1 1 > R1, the immune-free infected steady state E∗ is globally asymptotically stable; while if R1>1, the antibody immune infected steady state E is globally asymptotically stable. Moreover, our results show that ignoring the saturation effects of antibody immune response or infection rate will result in an overestimate of the antibody immune reproductive number. Copyright © 2016 John Wiley & Sons, Ltd.

N6 -methyladenosine (m6 A) is the most abundant internal chemical modification in eukaryotic messenger RNAs (mRNAs). The discovery in 2011 that m6 A is reversed by the fat mass and obesity-associated protein stimulated extensive worldwide research efforts on the regulatory biological functions of dynamic m6 A and other RNA modifications. The epitranscriptomic mark m6 A is written, read, and erased through the activities of a complicated network of enzymes and other proteins. m6 A-binding proteins read m6 A marks and transduce their downstream regulatory effects by altering RNA metabolic processes. In this review, we summarize the current knowledge of m6 A modifications, with particular focus on the functions of its writer, eraser, and reader proteins in posttranscriptional gene regulation and discuss the impact of m6 A marks on human health. This article is categorized under: RNA Processing > RNA Editing and Modification RNA in Disease and Development > RNA in Disease.

Aberrant expression of high mobility group box 1 (HMGB1) is associated with tumor development and progression. The current study was conducted to evaluate the significance of HMGB1 immunostaining on cell block (CB) preparations in the diagnosis of neoplastic and preneoplastic lesions of the cervix. The CBs were prepared from 157 residual liquid-based gynecologic cytology specimens which were collected from women whose cervical lesions had been confirmed by histopathology. The expression of HMGB1 and p16INK4A (p16) was visualized by immunocytochemistry on the CB preparations, and the association of their expression patterns was correlated with the severity of cervical lesions. HeLa cells were used as positive control. HMGB1 expression was observed in dysplastic and neoplastic cells and increased along with the progression of cervical neoplasia. The rates of positive staining for HMGB1 in cervical intraepithelial neoplasia 1 (CIN-1), CIN-2, CIN-3, and invasive squamous cell carcinomas (ISCCs) were 69.4, 96.9, 100.0, and 100.0%, respectively. The differences between positive rates of patients with chronic cervicitis and various CINs as well as ISCCs were significant (P

The SiN-passivated AlGaN/GaN high electron mobility transistors were investigated by 1MeV neutron irradiation at fluences up to 1015 cm-2, yielding a significant degradation for the transconductance near the knee voltage and the reverse gate leakage current at fluences ranging from 1014 to 1015 cm-2 which could be attributed to the irradiation induced mobility shift and the defects in SiN passivation layers respectively since no any recovery was found after 20 hour annealing at room temperature. Meanwhile the negligible degradation of the saturation drain current, the maximal transconductance and the threshold voltage gave the fact that the effectiveness of SiN layers in passivated surface states in the source-gate spacer and gate-drain spacer was undiminished by neutron irradiation. Moreover the ohmic contact was robustness to neutron since the sheet resistance of ohmic contact region hardly shifted, but the schottky characteristics degraded obviously. (© 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim)

A series of new chiral phosphine-aminophosphine ligands [(R)-HW-Phos] has been prepared from (R)-l.,2,3,4-tetrahydro-1-naphthylamine through a two-step procedure, and successfully applied in the rhodium-catalyzed asymmetric hydrogenation of various functionalized olefins such as alpha-enol ester phosphonates, alpha-enamido phosphonates, (Z)-beta-(acylamino)acrylates and so on. Excellent enantioselectivities have been achieved in the hydrogenation of most substrates tested, demonstrating the high potential of these newly developed phosphine-aminophosphine ligands in asymmetric catalysis. The present research also discloses that these newly developed phosphine-aminophosphine ligands are more efficient than that derived from (S)-1-phenyl ethyl amine, suggesting that the increased rigidity conferred by a cyclohexyl fragment in these phosphine-aminophosphine ligands has a positive effect in the asymmetric induction.

A series of chiral beta-substituted alkane-phosphonates was synthesized in high enantioselectivities via the first rhodium-catalyzed asymmetric hydrogenation of the corresponding beta-substituted-alpha,beta-unsaturated phosphonates using a ferrocene-derived rnonophosphoramidite ligand, with which up to 99.5% ee have been achieved for the hydrogenation of (E)-substrates and 98.0% ee for (Z)-substrates.

We have recently reported a new chiral 1,2,3,4-tetrahydro-1-naphthylamine-derived phosphine-phosphoramidite ligand, (R-c,R-a)-THNAPhos, that is highly efficient in the rhodium-catalyzed asymmetric hydrogenation of a broad range of alpha-enol ester phosphonates. To further demonstrate the utility of THNAPhos in asymmetric hydrogenation, in this paper, we describe its new application in the asymmetric hydrogenation of alpha-dehydroamino acid esters, enamides, dimethyl itaconate and alpha-enamido phosphonates. The results disclosed that the Rh/(R-c,R-a)-THNAPhos complex is highly effective for the enantioselective hydrogenation of these kinds of functionalized C=C olefins, affording the corresponding hydrogenation product in excellent enantioselectivities (normally over 99% ee).

Optically active a-hydroxy phosphonic acid derivatives are widely used as enzyme inhibitors, antibacterial agents, antiviral agents, antibiotics, anticancer agents, and pesticides, as well as useful building blocks for the synthesis of many other important a-functionalized optically active phosphonates. Therefore, an enantioselective synthesis of these compounds is highly desirable. Asymmetric catalysis has provided several novel solutions for the synthesis of chiral a-hydroxy phosphonic acid derivatives, including asymmetric reduction of ketophosphonates and phosphonylation of carbonyl compounds. For its inherent efficiency and atom economy, much effort in the past few years has been directed toward the development of an asymmetric hydrogenation of a-enol esters of phosphonate substrates. By this means, b-alkyl-substituted a-acyloxy phosphonates were hydrogenated with good enantioselectivities by using Rh catalysts bearing DuPHOS (1,2bis((2R,5R)-2,5-dialkylphospholano)benzene), BisP* ((S,S)1,2-bis(alkylmethylphosphino)ethane), MiniPHOS (R,Rbis(alkylmethylphosphino)methane),and phosphine–phosphite ligands. However, catalyst performance for b-aryland b-alkoxy-substituted substrates was less than satisfactory, as moderate enantioselectivities or low conversions were observed in most cases. Recently, Pizzano and co-workers reported that the use of a phosphine–phosphite/Rh catalyst could give rise to an ee value of up to 92% in the asymmetric hydrogenation of baryl-substituted substrates, although only the b-phenyl-substituted substrate afforded an ee value over 90% under full conversion. As for the hydrogenation of b-alkoxy-substituted substrates, there is only one report on the asymmetric hydrogenation of this class of substrates, in which 87% ee was obtained. Therefore, the highly enantioselective synthesis of a-hydroxy phosphonate derivatives by asymmetric hydrogenation of a-enol ester phosphonates, especially those bearing b-aryl or b-alkoxy substituents, is still a significant challenge for organic chemists. Herein, we report a new chiral phosphine–phosphoramidite ligand derived from (Rc)-1,2,3,4tetrahydro-1-naphthylamine (Rc= central chirality), which promoted unprecedented enantioselectivities (up to 99.9% ee) in Rh-catalyzed asymmetric hydrogenation across a broad range of substrates bearing b-aryl, b-alkoxy, and balkyl substituents. Ligand design has played a pivotal role in the development of efficient metal-catalyzed asymmetric reactions. Although a large number of bidentate phosphorus ligands with C2 symmetry or two closely related binding sites have been prepared and examined for asymmetric hydrogenation, significantly fewer unsymmetrical hybrid bidentate phosphorus ligands were disclosed. We and others have recently revealed that chiral phosphine–phosphoramidite ligands are highly efficient for the asymmetric hydrogenation of various functionalized olefins, including aand b-dehydroamino acid esters, itaconate, and enamides. In our ongoing efforts toward the development of new and practical chiral ligands for use in the hydrogenation of challenging substrates, we designed a class of rigid chiral phosphine–phosphoramidite ligands with a 1,2,3,4-tetrahydronaphthalene backbone. The phosphine–phosphoramidite ligands 1 can be readily prepared from optically pure (Rc)-1,2,3,4-tetrahydro-1-naphthylamine ((Rc)-2) through a concise synthetic procedure (Scheme 1). The initial step involves functionalization of

The title reaction proceeds under mild conditions and is suitable for a broad range of substrates providing optically active propargylic amines in high yields with high enantioselectivities.

Novel sulfur-containing compounds ( 3a – 3c , 4a – 4c ) were obtained in ethanol with 1,3-diphenyl-2-propanone as the starting material. The advantages of this procedure were mild reaction conditions, simple protocol, and high yields. The structures of the products were characterized by IR, 1 H NMR, MS and elementary analysis. The crystal of the new compound 4a belongs to monoclinic, space group C2 with a = 18.727(3), b = 6.5179(9), c = 13.7576(18) A, β = 131.0610(10)°, V = 1266.2(3)A 3 , Z = 2, Dc = 2.136 g/cm 3 , μ = 1.078 mm −1 , F (0 0 0) = 843, R = 0.0490 and wR = 0.1247 for 3211 observed reflection with I > 2 σ ( I ). X-ray analysis reveals that the molecule is not symmetrical, the molecular structure is stabilized by weak π – π stacking interactions, and no classical hydrogen bonds can be observed.

A diversity of enantio-enriched β-branched phosphonates is obtained by Rh-catalyzed hydrogenation of α,β-unsaturated phosphonates in the presence of chiral Walphos ligand.

A microwave-assisted three-step sequence allows the synthesis of the title compounds (VI) as pharmaceutically interesting frameworks.

The asymmetric conjugate reduction of 3-aryl-4-phosphonobutenoates has been demonstrated which provides an enantioselective synthesis of optically active 3-aryl-4-phosphonobutyric acid esters. A wide range of 3-aryl-4-phosphonobutenoate derivates are reduced with high enantioselectivities (up to 94% ee) using an ( S )-Segphos/Cu(OAc) 2 ·H 2 O catalyst system (1 or 5 mol %) in the presence of PMHS and t -BuOH. The reduction is influenced by the steric and electronic effects of the substrates.

The method allows an efficient and highly enantioselective access to phosphonates of type (II) and can be applied to prepare the potential GABAB antagonist (R)-phaclofen (V).

An enantioselective synthesis of chiral alkylphosphonates bearing a β-stereogenic center, based on the Rh-catalyzed asymmetric hydrogenation of corresponding β-substituted β,γ-unsaturated phosphonates with a ferrocene-based monophosphoramidite ligand under the mild hydrogenation conditions, was developed, in which an ee value of up to 98% was obtained.

A series of chiral alkylphosphonates bearing β-stereogenic center were synthesized in good enantioselectivities (up to 95% ee) via the CuH-catalyzed asymmetric conjugate reduction of β-substituted α,β-unsaturated phosphonates under optimal conditions using Cu(OAc)2·H2O as the copper source, (R)-SEGPHOS as the ligand, PMHS as the siloxane, and t-BuOH as the additive.

A new class of chiral ferrocenyl diphosphine ligands with an imidazole ring, (R(c), S(Fc))-ImiFerroPhos, has been prepared from acylferrocenes through a five-step transformation and successfully applied in the Rh-catalyzed asymmetric hydrogenation of various 3-aryl-substituted 2-phosphonomethylpropenoates, in which a series of chiral 3-phosphono-2-arylmethylpropanoic acid derivatives were achieved in ee values of up to 98%.

An enantioselective synthesis of optically active 1-aryl or 1-alkyl substituted ethylphosphonates, based on the first Rh-catalyzed asymmetric hydrogenation of corresponding α,β-unsaturated precursors with a P-stereogenic BoPhoz-type ligand under the mild condition, was developed, in which a wide range of 1-aryl or 1-alkyl substituted ethylphosphonates were achieved in up to 98% ee.

A series of chiral ferrocene-based phosphine–phosphoramidite ligands (PPFAPhos) have been employed in the Ag(I)-catalyzed asymmetric [3+2] cycloaddition of azomethine ylides with dimethyl maleate. The results showed that the ligand with a stereogenic P-center in the phosphino moiety displayed the best diastereo- and enantioselectivities, in which up to 99% enantiomeric excesses and 99/1 endo/exo selectivities have been achieved.

A new family of chiral bis(1-ferrocenylethyl)amine-derived monodentate phosphoramidite ligands has been prepared and successfully applied in the Cu-catalyzed asymmetric 1,4-conjugate addition of diethylzinc to a variety of α,β-unsaturated compounds, in which up to 99% ee was obtained for nitroalkenes at −78 °C and >98% ee for cyclohexenone at −30 °C, comparable to or higher than those obtained with the most efficient monophosphoramidite ligands reported so far.