Boryl radical catalysis enables asymmetric radical cycloisomerization reactions.

The development of functionally distinct catalysts for enantioselective synthesis is a prominent yet challenging goal of synthetic chemistry. In this work, we report a family of chiral N-heterocyclic carbene (NHC)-ligated boryl radicals as catalysts that enable catalytic asymmetric radical cycloisomerization reactions. The radical catalysts can be generated from easily prepared NHC-borane complexes, and the broad availability of the chiral NHC component provides substantial benefits for stereochemical control. Mechanistic studies support a catalytic cycle comprising a sequence of boryl radical addition, hydrogen atom transfer, cyclization, and elimination of the boryl radical catalyst, wherein the chiral NHC subunit determines the enantioselectivity of the radical cyclization. This catalysis allows asymmetric construction of valuable chiral heterocyclic products from simple starting materials.

Sequential C-F bond functionalizations of trifluoroacetamides and acetates via spin-center shifts.

Defluorinative functionalization of readily accessible trifluoromethyl groups constitutes an economical route to partially fluorinated molecules. However, the controllable replacement of one or two fluorine atoms while maintaining high chemoselectivity remains a formidable challenge. Here we describe a general strategy for sequential carbon-fluorine (C-F) bond functionalizations of trifluoroacetamides and trifluoroacetates. The reaction begins with the activation of a carbonyl oxygen atom by a 4-dimethylaminopyridine-boryl radical, followed by a spin-center shift to trigger the C-F bond scission. A chemoselectivity-controllable two-stage process enables sequential generation of difluoro- and monofluoroalkyl radicals, which are selectively functionalized with different radical traps to afford diverse fluorinated products. The reaction mechanism and the origin of chemoselectivity were established by experimental and computational approaches.

Direct Csp3-H methylenation of 2-arylacetamides using DMF/Me2NH-BH3 as the methylene source.

A direct Csp3-H methylenation of 2-arylacetamides using DMF/Me2NH-BH3 as the methylene source was developed. The formyl group of DMF delivered the carbon and one hydrogen atoms, and the Me2NH-BH3 donated the remaining one hydrogen atom. This protocol offers a new alternative to make useful 2-arylacrylamides from simple starting materials.

CRMP2 and CRMP4 Are Differentially Required for Axon Guidance and Growth in Zebrafish Retinal Neurons.

Axons are directed to their correct targets by guidance cues during neurodevelopment. Many axon guidance cues have been discovered; however, much less known is about how the growth cones transduce the extracellular guidance cues to intracellular responses. Collapsin response mediator proteins (CRMPs) are a family of intracellular proteins that have been found to mediate growth cone behavior in vitro; however, their roles in vivo in axon development are much less explored. In zebrafish embryos, we find that CRMP2 and CRMP4 are expressed in the retinal ganglion cell layer when retinal axons are crossing the midline. Knocking down CRMP2 causes reduced elongation and premature termination of the retinal axons, while knocking down CRMP4 results in ipsilateral misprojections of retinal axons that would normally project to the contralateral brain. Furthermore, CRMP4 synchronizes with neuropilin 1 in retinal axon guidance, suggesting that CRMP4 might mediate the semaphorin/neuropilin signaling pathway. These results demonstrate that CRMP2 and CRMP4 function differentially in axon development in vivo.

Thomsen-Friedenreich activation in infants with necrotizing enterocolitis in Taiwan.

BACKGROUND: Thomsen-Friedenreich (T) activation in infants with neonatal necrotizing enterocolitis (NEC) has in some cases led to severe hemolysis after transfusions of plasma-containing blood components, causing some authors to advise routine screening for T activation in all infants with NEC. However, no data are available on the frequency of T activation in infants with NEC in Taiwan. STUDY DESIGN AND METHODS: We retrospectively reviewed the medical records of 43 infants with NEC managed in our hospital from 2000 to 2007. In all cases, Arachis hypogaea lectin was used to test for T activation. RESULTS: Of the 43 infants, 16 infants (37%) had Stage II and 27 (63%) had Stage III NEC. Four infants had trace T activation, two of whom received transfusions with washed red blood cells (RBCs) and two with unwashed RBCs. None had evidence of hemolysis. The overall mortality in this series was 16% (7/43), but none of the four babies with T activation died. CONCLUSION: In this series of Taiwanese infants with NEC, weak T activation was present in only 9% (4/43) of infants, and RBC transfusion did not result in hemolysis, regardless of whether washed or unwashed cells were administered. We considered routine screening for T activation and provision of prepared blood components in infants with NEC in Taiwan might be unnecessary.

[The analysis of fundus fluorescein angiography, indocyanine green angiography and hemodynamics of retrobulbar blood vessels in central serous chorioretinopathy].

OBJECTIVE: To analyze the characteristics of the retrobulbar blood vessels' hemodynamics changes and the choroidal circulation disorder, and to observe the relations between retinal pigment epithelium's (RPE) pathological changes and them. METHODS: It was a case control study. For 57 (57 affected eyes and 57 contralateral eyes) unilateral eye affected patients and 25 (50 eyes) normal health adults, we examined ophthalmic arteries (OA), posterior ciliary arteries (PCA) and short posterior ciliary arteries (SPCA) by color Doppler flow Imaging (CDFI), and recorded the peak systolic velocities (PSV), end diastolic velocities (EDV) and resistance indexes (RI) of them. We compared each hemodynamic parameter of the normal eyes with it of the affected eyes and contralateral eyes in patients group respectively, and contrasted them between affected eyes and contralateral eyes of the patients. Fundus fluorescein angiography (FFA) and indocyanine green angiography (ICGA) were performed simultaneously on 57 patients with Heidelberg retina angiography, and the images were analyzed in contrast. We used SPSS 12.0 statistics software was used in the study. To the PSV, EDV and RI of the OA, PCA and SPCA in affected eyes and contralateral eyes of the patients, we used paired t-test for the same sample to compare their hemodynamic parameters; to compare normal health adults' eyes with the affected eyes and the contralateral eyes of patients group respectively, we used two-group t-test. When the P-value was less than 0.05, there was a statistical significance. RESULTS: There was a more significant decrease of the hemodynamic parameters in both PSVs and EDVs of temporal PCAs (PSV: t = 3.044, P = 0.005; EDV: t = 3.731, P = 0.001) and temporal SPCAs (PSV: t = 2.822, P = 0.008; EDV: t = 3.194, P = 0.003) compared the patients group's affected eyes with normal health adults group eyes, there was a more significant decrease of them of temporal PCAs (PSV: t = 3.219, P = 0.003; EDV: t = 3.807, P = 0.001) and temporal SPCAs (PSV: t = 3.931, P = 0.000, EDV: t = 3.145, P = 0.003) compared the patients group's contralateral eyes with normal health adults group eyes, and there was a statistical significance of them (P < 0.05). There was no difference in hemodynamic parameters of both PSVs and EDVs of temporal PCAs (PSV: t = 0.608, P = 0.548; EDV: t = 0.122, P = 0.904) and temporal SPCAs (PSV: t = 0.730, P = 0.470; EDV: t = 0.109, P = 0.914) between affected eyes and contralateral eyes of the patients, and there was no statistical significance of them (P > 0.05). The results of FFA and ICGA showed that all the RPE's leaks of 57 affected eyes appeared at the hypofluorescent regions of relative choroids; 52 cases of 57 affected eyes were followed by choroidal vessels dilatation at the early hypofluorescent regions, and appeared hyperfluorescence leakages in the late phase images; At the all regions of RPE's transmitted fluorescences of affected eyes and contralateral eyes, the corresponding choroids showed hyperfluorescence in the late phase images in ICGA; There were no RPE's transmitted fluorescences at the regions of 20 affected eyes and 16 contralateral eyes in FFA, which showed hyperfluoresceince leakages in the late phase images of choroids in ICGA. CONCLUSIONS: CSC is possibly a bilateral disease associated with systemic pathologic conditions. Hypoperfusion and ischemia are the basal characteristics of retrobulbar blood vessels' circulation disorder and choroidal ultracirculation disorder. The damage of RPE is following to the choroidal circulation disorder.

Primary autoimmune neutropenia in children in Taiwan.

BACKGROUND: Autoimmune neutropenia in children is caused by granulocyte-specific autoantibodies. These antibodies react to the patient's own neutrophils but disappear when the neutropenia spontaneously remits. This study reviewed our experience with autoimmune neutropenia in children and investigated possible associations with HLA-DR and HLA-DQ alleles. STUDY DESIGN AND METHODS: From 1993 to 2006, our laboratory received 155 blood samples from children with neutropenia. Of these samples, 55 had granulocyte-specific autoantibodies on the indirect granulocyte immunofluorescence test. As the children had no other disorders associated with neutropenia, they were diagnosed with primary autoimmune neutropenia. HLA-DRB1 and -DQB1 allele typing was performed in 31 cases, and the results were compared with those of 190 normal healthy unrelated Taiwanese controls. RESULTS: The mean ages of onset and resolution of neutropenia were 9.8 months (median, 9.0 months; range, 4-28 months) and 22.5 months (median, 20.0 months; range, 13-44 months), respectively. The male-to-female ratio was 1.2:1. The mean absolute neutrophil count was 190 per microL (standard deviation, 213/microL). Most patients (74%) had antibodies against HNA-1a. Autoimmune neutropenia in children in Taiwan was significantly associated with HLA-DQB1*0503 (odds ratio, 6.48; p = 0.0002; p(c) = 0.003) allele. CONCLUSION: In Taiwan, autoimmune neutropenia in children is associated with HLA-DQB1*0503. The autoantibody in autoimmune neutropenia is most commonly anti-HNA-1a.

Anti-"Mi(a)" immunization is associated with HLA-DRB1*0901.

BACKGROUND: Anti-"Mi(a)" is one of the most important irregular red blood cell antibodies found in Taiwan. The aim of this study was to investigate whether specific HLA-DRB1 alleles are associated with anti-"Mi(a)" production. STUDY DESIGN AND METHODS: A case-control retrospective study was performed on 68 patients showing presence of anti-"Mi(a)" and 219 unrelated control subjects from the Mackay Memorial Hospital. HLA-DRB1 genotyping was carried out using sequence-based typing method. Fisher's exact test using 2 x 2 contingency tables was used to analyze significance of the association between DRB1 polymorphisms and presence of anti-"Mi(a)" in patients. RESULTS: HLA-DRB1*0901 allele frequency in the anti-"Mi(a)" group (30%) was significantly higher than in the control group (16%) with an odds ratio of 2.27 (95% confidence interval, 1.44-3.55; p = 0.0005; p(c) = 0.016). CONCLUSION: HLA-DRB1*0901 is significantly more prevalent in the anti-"Mi(a)" patients group than in the control group. It is suggested that cells from DR9 individuals might present processed "Mi(a)" antigen-allospecific peptides more effectively than cells from individuals carrying other DR phenotypes. Finally, it was predicted that two epitopes, derived from the MiIII glycophorin amino acid sequence, were likely to bind preferentially with the DR9 molecule. Further work will be necessary to determine if these epitopes are responsible for anti-"Mi(a)" alloimmunization.

Structure-activity study on the spatial arrangement of the third aromatic ring of endomorphins 1 and 2 using an atypical constrained C terminus.

The discovery of endomorphins (EMs) has opened the possibility of searching for new analgesics. However, the design of peptide analgesics has proven to be very difficult as a result of their conformational flexibility and a lack of clarity in structure-activity relationships (SAR). In EMs, the amino acid side chains exhibit considerable conformational flexibility, especially in the third aromatic ring, which is free to adopt a bioactive conformation. To resolve these problems, a series of C terminus EM analogues, [Xaa(4)-R]EMs, modified through the substitution of Phe(4) with nonaromatic residues and termination with benzyl groups, were designed to generate conformational constrains of the third aromatic ring by amide bond and torsion angles (phi(4) and psi(4)) of Xaa(4). Introduction of (S)-alpha-methyl or (S)/(R)-alpha-carboxamide on the methylene unit of the benzyl group was designed to produce an atypical topographical constraint (phi(5)) of the third aromatic ring rotation. Interestingly, some EM derivatives, with elimination of the C-terminal carboxamide group and significant changes in the address sequence (Phe(4)-NH(2)), still exhibited higher mu-opioid receptor (MOR) affinity than unmodified EMs. In contrast, some analogues with incorrectly constrained C termini displayed very low affinity and pharmacological activities. Thus, our results indicate that these EM analogues, with atypical constrained C termini, provide model compounds with potent MOR agonism. They also give evidence that the proper spatial orientation and conformational restriction of the third aromatic ring are crucial for the interaction of EMs with MOR.