Au(I)-Catalyzed Regioselective Hydrofluorination of Propargylamines Using Aqueous HF.

Gold-catalyzed regioselective hydrofluorination of alkynes using aqueous HF has been achieved by employing an amide directing group. For both aryl- and alkyl-substituted propargylamines, the fluorination occurred at the site distal to the amino group.

Gold catalyzed hydrofluorination of propargyl alcohols promoted by fluorine-hydrogen bonding.

The hydroxyl group was discovered to promote gold catalyzed hydrofluorination of alkynes via hydrogen bonding interaction. Based on this strategy, propargyl alcohols could be hydrofluorinated smoothly using Et3N·3HF under acidic additive-free conditions, which provided a straightforward alternative protocol for the synthesis of 3-fluoroallyl alcohols.

A one-step base-free synthesis of N-arylamides via modified pivaloyl mixed anhydride mediated amide coupling.

Pivalic anhydride is shown to be an effective reagent for direct amidation of carboxylic acids with N-alkyl anilines. The only by-product of this reaction is nontoxic pivalic acid, which can be easily removed by aqueous workup. The reactions are conducted under mild conditions and found to be compatible with a range of carboxylic acids, including aromatic, heterocyclic, acrylic, and aliphatic carboxylic acids and amino acids generating the desired amides in short reaction times.

Dual Integrating Oxygen and Sulphur on Surface of CoTe Nanorods Triggers Enhanced Oxygen Evolution Reaction.

The bottleneck of large-scale implementation of electrocatalytic water-splitting technology lies in lacking inexpensive, efficient, and durable catalysts to accelerate the sluggish oxygen evolution reaction kinetics. Owing to more metallic features, transition metal telluride (TMT) with good electronic conductivity holds promising potential as an ideal type of electrocatalysts for oxygen evolution reaction (OER), whereas most TMTs reported up to now still show unsatisfactory OER performance that is far below corresponding sulfide and selenide counterparts. Here, the activation and stabilization of cobalt telluride (CoTe) nanoarrays toward OER through dual integration of sulfur (S) doping and surface oxidization is reported. The as-synthesized CoO@S-CoTe catalyst exhibits a low overpotential of only 246 mV at 10 mA cm-2 and a long-term stability of more than 36 h, outperforming commercial RuO2 and other reported telluride-based OER catalysts. The combined experimental and theoretical results reveal that the enhanced OER performance stems from increased active sites exposure, improved charge transfer ability, and optimized electronic state. This work will provide a valuable guidance to release the catalytic potential of telluride-based OER catalysts via interface modulating engineering.

Complementary Oxidative Generation of Iminyl Radicals from α-Imino-oxy Acids: Silver-Catalyzed C-H Cyanoalkylation of Heterocycles and Quinones.

A complementary and general strategy for the oxidative generation of iminyl radicals from the readily available α-imino-oxy acids has been established through silver-catalyzed decarboxylation. To demonstrate its synthesis utility, the direct C-H cyanoalkylation of heterocycles and quinones with cyclic α-imino-oxy acids via the iminyl radical-mediated C-C bond cleavage is developed. This cost-effective method takes place under mild reaction conditions and exhibits a broad substrate scope.

General 5-Halomethyl Isoxazoline Synthesis Enabled by Copper-Catalyzed Oxyhalogenation of Alkenes.

A general and efficient oxyhalogenation of unsaturated ketoximes has been achieved through copper catalysis with diethyl bromomalonate, N-chlorosuccinimide, and N-iodosuccinimide, yielding 5-chloromethyl, 5-bromomethyl, and 5-iodomethyl isoxazolines in good to excellent yields.

Blocking CD226 Promotes Allogeneic Transplant Immune Tolerance and Improves Skin Graft Survival by Increasing the Frequency of Regulatory T Cells in a Murine Model.

BACKGROUND/AIMS: Regulatory T cells (Tregs) play key roles in maintaining peripheral tolerance and preventing autoimmune disease. Treg modulation could be helpful in treating malignancies, autoimmune disease, and allergies, as well as to facilitate organ transplantation. Signals transduced by co-stimulatory molecules are essential for Treg differentiation, homeostasis, and function. One well-known active receptor, CD226, also known as DNAM-1 or PTA1, is an adhesion molecule that interacts primarily with CD155 and is involved in Treg differentiation and immune tolerance to transplanted tissue. METHODS: Anti-CD226 monoclonal antibody (mAb) and truncated recombinant CD226 proteins were employed to manipulate the CD226 signal. Various T cell markers on freshly isolated splenocytes and T lymphocytes were characterized by flow cytometry Cell proliferation was measured by carboxyfluorescein succinimidyl ester dye, mRNA transcripts by q-RT PCR, and protein expression by western blotting. A BALB/c-to-C57BL/6 skin allograft model was used to determine the effects of CD226 blocking treatment. RESULTS: We observed that both intact extracellular domains of CD226 were necessary for functional interaction of the receptor with its ligand CD155, even though one domain was shown to bind CD155 with lower affinity in a solid binding assay. Importantly, CD226 mAb promoted Treg expansion in a mixed lymphocyte culture and inhibited the cytotoxicity of effector cells. In allogeneic skin transplant mice, administering CD226 mAb reduced inflammation and prolonged allogeneic graft survival, with an increase in the frequency of Tregs. CONCLUSIONS: Our results reveal the mechanism underlying CD226-CD155 interactions and indicate that CD226 signals can be manipulated to promote Treg expansion. Moreover, we provide new evidence that suggests the therapeutic potential of anti-CD226 with allogeneic transplantation.

Tetrabutylammonium iodide-catalyzed oxidative coupling of enamides with sulfonylhydrazides: synthesis of ß-keto-sulfones.

A facile synthetic route towards pharmaceutically interesting ß-keto-sulfone derivatives by tetrabutylammonium iodide (TBAI)/tert-butyl hydroperoxide (TBHP) mediated oxidative coupling of readily prepared enamides with economical sulfonylhydrazides is described. The corresponding ß-keto-sulfone compounds were obtained in moderate to good yields. The present method is metal-free and base-free and shows tolerance to a variety of functional groups.

Reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.

B cells play an important role in the clearance of hepatitis B virus (HBV) and protection against reinfection. However, the functional characteristics of these cells that are associated with the outcome of chronic HBV infection remain unknown. We comprehensively investigated the frequency, phenotype, and function of peripheral B-cell subsets from CHB patients in different phases: immune tolerance (IT), immune activation (IA), immune clearance (IC), responders with HBsAg seroconversion (resolved patients, RP), and healthy controls (HC). IA patients displayed lower percentages of peripheral blood memory B cells compared with the other groups. Overall polyclonal activation of B cells, indicated by higher levels of activation markers and secretion of IgG and IgM, was observed in IA patients. This B-cell hyperactivation could be induced by increased IFN-α and soluble CD40 ligands in IA patients. Notably, the expression of the co-stimulator molecule CD80 and serum HBsAb and the frequency of HBsAg-specific B cells were significantly decreased in IT, IA, and IC patients compared with HC subjects. More importantly, the B-cell hyperactivation, co-stimulatory molecule downregulation and HBsAg-specific B-cell impairment were reversed in RP patients. The reversal of B-cell hyperactivation and functional impairment is associated with HBsAg seroconversion in chronic hepatitis B patients.

Metal-free TBAI-catalyzed arylsulfonylation of activated alkenes with sulfonylhydrazides.

An efficient metal-free oxidative arylsulfonylation of α,ß-unsaturated imides with sulfonylhydrazides leading to isoquinoline-1,3(2H,4H)-dione derivatives has been developed. The procedure involves the generation of sulfonyl radicals via cleavage of the S-N bond of sulfonylhydrazides with sulfonylation and C-H functionalization. The protocol uses the economical and environmentally friendly TBAI-TBHP catalytic system, and the corresponding isoquinoline-1,3(2H,4H)-diones with various functional groups were obtained in moderate to good yields.

CXCR5+ CD4+ T follicular helper cells participate in the pathogenesis of primary biliary cirrhosis.

UNLABELLED: There is increasing interest in the role of T follicular helper (Tfh) cells in autoimmunity from the perspective of both their role in breach of tolerance and their effects on the natural history of disease progression. Indeed, the critical role of Tfh cells in autoimmunity is further highlighted based on their location in the germinal center (GC), a pathogenic hot spot for development of autoreactivity. To address the role of Tfh cells in primary biliary cirrhosis (PBC), we comprehensively evaluated the immunobiology of CXCR5(+) CD4(+) Tfh cells in 69 patients with PBC, including a nested subgroup of 16 autoimmune hepatitis (AIH) and 20 healthy controls (HC), followed for 1 year. We report herein several key observations. First, there was an increased frequency of circulating Tfh cells in patients with PBC compared to AIH (P < 0.05) and HC (P < 0.01). Second, the function of circulating Tfh cells from PBC patients, including interleukin (IL)-21 production (P < 0.05), the ability to promote B-cell maturation, and autoantibody production, were greater than HC. Third, the frequency of these cells was significantly decreased in ursodeoxycholic acid (UDCA) responders compared to UDCA-treated nonresponders, in both cross-sectional (P = 0.023) and longitudinal studies (P = 0.036), respectively. Indeed, similar increases of Tfh cells were noted in liver and spleen. CONCLUSION: These results significantly extend our understanding of lymphoid subpopulations in PBC and their relative role in disease expression. Our data also provide a novel biomarker for evaluation of the effectiveness of new therapeutic approaches.

[CD160 characterization and its association with disease progression in patients with chronic HIV-1 infection].

OBJECTIVE: To explore the expression of CD160, a costimulator, on CD4(+) and CD8(+) T cells in chronic human immunodeficiency virus-1 (HIV-1) infected patients. METHODS: A total of 23 chronic HIV-1 infected patients were enrolled into 302 Hospital of People's Liberation Army from January 2010 to December 2011. Meanwhile, 20 healthy individuals were selected as healthy controls (HC). Peripheral blood was collected, peripheral blood mononuclear cells (PBMC) were isolated by density gradient centrifugation and CD160 was stained with fluorescent antibody. The expressions of CD160 on CD4(+) and CD8(+) T cell subsets were detected by flow cytometry and its correlation with CD4(+) T cell absolute number and HIV RNA viral load were analyzed. RESULTS: The expressions of CD160 on CD4(+) and CD8(+) T cell increased versus HC (on CD4(+) T cells, percentage: (14.3 ± 7.5)% vs (3.9 ± 2.2)%, median fluorescent intensity (MFI): 26.4 ± 11.0 vs 12.4 ± 2.9; on CD8(+) T cells, percentage: (40.9 ± 13.2)% vs (12.9 ± 6.6)%, MFI: 52.5 ± 17.4 vs 18.2 ± 5.0). Furthermore, the expression of CD160 on CD4(+) T cells was negatively correlated with CD4(+) T cell absolute number (r = -0.550, P = 0.010) and positively with HIV RNA load (r = 0.522, P = 0.015). However, the expression of CD160 on CD8(+) T cells was not correlated with CD4(+) T cell absolute number or HIV RNA load. The expressions of CD160 on CD8(+) T cell subsets Tn, Tcm and Tem in patients with chronic HIV-1 infection increased compared with HC (25.3 ± 17.6 vs 5.0 ± 3.1, 45.8 ± 13.0 vs 20.4 ± 4.3, 37.0 ± 13.6 vs 20.0 ± 10.8). In addition, Tn subset decreased while Tcm subset increased in CD160(+) CD8(+) T cell subset distribution in patients with HIV-1 infection compared with HC subjects. CONCLUSION: CD160 may contribute to the exhaustion of CD4(+) and CD8(+) T cells and influence the distribution of memory CD8(+) T cell subsets.

Iron-catalyzed arylalkoxycarbonylation of N-aryl acrylamides with carbazates.

A novel arylalkoxycarbonylation of N-aryl acrylamides with carbazates leading to alkoxycarbonylated oxindoles has been developed. The reported reactions employ economical and environmentally benign FeCl2·4H2O as a catalyst and easily accessible and safe carbazates as alkoxycarbonyl radical precursors.

Interleukin-21 mediates hepatitis B virus-associated liver cirrhosis by activating hepatic stellate cells.

AIM: Interleukin-21 (IL-21) is involved in effective primary hepatic immune response against hepatitis B virus (HBV) and profibrotic function. However, the role of IL-21 in HBV-associated liver cirrhosis is poorly understood. This study aimed to investigate the role of IL-21 in HBV-associated liver cirrhosis and possible mechanisms. METHODS: The study subjects included 10 healthy controls and 30 patients with HBV-associated liver cirrhosis that categorized into three subgroups based on Child-Pugh score (A, 13; B, 10; C, 7). The frequencies of IL-21(+) CD4(+) T cells were detected by flow cytometry, and the level of IL-21 in plasma was measured by enzyme-linked immunoassay. The distribution of IL-21(+) cells in situ in liver was observed by immunohistochemistry. In addition, the in vitro expression of α-smooth muscle actin (α-SMA), apoptosis and proliferation markers of LX-2 cells were examined by flow cytometry and Cell Counting Kit-8 kit. Finally, the collagen levels in the supernatant were measured by chemiluminescence. RESULTS: Increased peripheral number of IL-21(+) CD4(+) cells, elevated plasma level of IL-21 and IL-21(+) cell accumulation in liver were observed in patients with HBV-associated liver cirrhosis. In vitro administration of IL-21 was accompanied with increased expression of α-SMA, inhibited LX-2 cells apoptosis and upregulated collagen production by LX-2 cells. CONCLUSION: IL-21 may contribute to the fibrogenesis of HBV-associated liver cirrhosis by activating the hepatic stellate cells. Therefore, neutralization of IL-21 could be a favorable new therapeutic strategy for liver cirrhosis treatment.

HCV-specific interleukin-21+CD4+ T cells responses associated with viral control through the modulation of HCV-specific CD8+ T cells function in chronic hepatitis C patients.

Interleukin-21 (IL-21)+CD4+ T cells are involved in the immune response against hepatitis B virus (HBV) by secreting IL-21. However, the role of IL-21+CD4+ T cells in the immune response against chronic hepatitis C (CHC) virus infection is poorly understood. This study aimed to investigate the role of IL-21+CD4+ T cells in CHC patients and the potential mechanisms. The study subjects included nineteen CHC patients who were grouped by viral load (low, < 10(6) RNA copies/ml, n = 8; high, > 10(6) RNA copies/ml, n = 11). The peripheral frequency of HCV-specific IL-21+CD4+ T cells was higher in the low viral load group and was negatively correlated with the serum HCV RNA viral load in all CHC patients. Meanwhile, IL-21+ cells accumulated in the liver in the low viral load group. In vitro, IL-21 treatment increased the expression of proliferation markers and cytolytic molecules on HCV-specific CD8+ T cells. In summary, these findings suggest that HCV-specific IL-21+CD4+ T cells might contribute to HCV control by rescuing HCV-specific CD8+ T cells in CHC patients.

Safety and immunological responses to human mesenchymal stem cell therapy in difficult-to-treat HIV-1-infected patients.

OBJECTIVE: HAART largely decreases morbidity and mortality in chronic HIV-1-infected patients, but immune nonresponders (INRs) with full viral suppression still fail to reverse the immune deficiency. This study evaluated the safety and immunological responses of human umbilical cord mesenchymal stem cell (MSC) therapy in HIV-1-infected INRs. DESIGN AND METHODS: A total of 13 HIV-1-infected INRs were enrolled in this pilot prospectively open-labeled controlled clinical trial. Seven patients were administered three umbilical cord-MSC transfusions at 1-month interval during 12-months of follow-up, whereas six control patients were treated with saline in parallel. Immunological parameters were monitored in these patients throughout the trial. RESULTS: All patients tolerated the umbilical cord-MSC transfusions well throughout the trial. The umbilical cord-MSC transfusions preferentially increased circulating naive and central memory CD4 T-cell counts and restored HIV-1-specific IFN-γ and IL-2 production in the INRs. These enhancements in immune reconstitution were also associated with the reduction of systemic immune activation and inflammation in vivo. CONCLUSIONS: umbilical cord-MSC transfusions are well tolerated and can efficiently improve host immune reconstitution in INRs, suggesting that such treatments may be used as a novel immunotherapeutic approach to reversing immune deficiency in HIV-1-infected INRs (ClinicalTrials.gov identifier: NCT01213186).

Iron halide-mediated regio- and stereoselective halosulfonylation of terminal alkynes with sulfonylhydrazides: synthesis of (E)-ß-chloro and bromo vinylsulfones.

Halosulfonylation of terminal alkynes was achieved with sulfonylhydrazides as the sulfonyl precursor and inexpensive iron halide as halide source in the presence of TBHP, allowing the regio- and stereoselective generation of (E)-ß-chloro and bromo vinylsulfones.

Synthesis of sulfonated oxindoles by potassium iodide catalyzed arylsulfonylation of activated alkenes with sulfonylhydrazides in water.

A catalytic system consisting of KI, 18-crown-6, and TBHP for arylsulfonylation of activated alkenes with sulfonylhydrazides as sulfonyl precursor is described. This protocol provides a practical and environmentally benign method for the construction of sulfonated oxindoles in water.

18F-fluorothymidine-pet imaging of glioblastoma multiforme: effects of radiation therapy on radiotracer uptake and molecular biomarker patterns.

Introduction. PET imaging is a useful clinical tool for studying tumor progression and treatment effects. Conventional (18)F-FDG-PET imaging is of limited usefulness for imaging Glioblastoma Multiforme (GBM) due to high levels of glucose uptake by normal brain and the resultant signal-to-noise intensity. (18)F-Fluorothymidine (FLT) in contrast has shown promise for imaging GBM, as thymidine is taken up preferentially by proliferating cells. These studies were undertaken to investigate the effectiveness of (18)F-FLT-PET in a GBM mouse model, especially after radiation therapy (RT), and its correlation with useful biomarkers, including proliferation and DNA damage. Methods. Nude/athymic mice with human GBM orthografts were assessed by microPET imaging with (18)F-FDG and (18)F-FLT. Patterns of tumor PET imaging were then compared to immunohistochemistry and immunofluorescence for markers of proliferation (Ki-67), DNA damage and repair (γH2AX), hypoxia (HIF-1α), and angiogenesis (VEGF). Results. We confirmed that (18)F-FLT-PET uptake is limited in healthy mice but enhanced in the intracranial tumors. Our data further demonstrate that (18)F-FLT-PET imaging usefully reflects the inhibition of tumor by RT and correlates with changes in biomarker expression. Conclusions. (18)F-FLT-PET imaging is a promising tumor imaging modality for GBM, including assessing RT effects and biologically relevant biomarkers.

Upregulation of OX40 ligand on monocytes contributes to early virological control in patients with chronic hepatitis C.

Dysfunctional hepatitis C virus (HCV) specific CD4(+) T cells are known to contribute to inadequate adaptive immunity in chronic hepatitis C (CHC), although the underlying mechanisms remain largely undefined. In this study, OX40 ligand (OX40L) expression was investigated in 41 treatment-naïve CHC patients, 20 sustained virological responders and 36 healthy subjects. We observed that OX40L expression was significantly upregulated in peripheral monocytes in CHC patients compared with sustained virological responders and healthy subjects. OX40L upregulation correlated significantly with plasma viral load rather than serum alanine aminotransaminase levels. Furthermore, longitudinal analyses indicated that upregulated OX40L expression on monocytes is closely associated with rapid or early virological responses in patients receiving pegylated IFN-α/ribavirin treatment. In vitro, HCV core antigen strongly stimulated monocyte expression of OX40L and blockade of TLR2 signaling significantly downregulated OX40L expression. More importantly, elevated OX40L expression was also shown to be closely associated with elevation of the HCV-specific CD4(+) T-cell response and in vitro blockade of OX40L expressed on monocytes led to impaired CD4(+) T-cell function. These findings, therefore, implicate OX40L expression can be used as a marker to evaluate antiviral treatment efficacy and extend the notion that enhancement of OX40L expression could be a good way for immunotherapy in CHC patients.