Random and block 2-alkyl-2-oxazolines telechelic macromonomers

Ring-opening polymerization of 2-methyl-2-oxazoline initiated by 2-(p-nitrobenzenesulfonato)ethyl methacrylate follows the so-called “living mechanism”, i.e. fast initiation compared to slow propagation and no chain transfer. Accordingly, methacryl macromonomers having homopolymers, block or random copolymers of 2-methyl and 2-pentyl-2-oxazoline backbones with narrow molecular weight distribution were obtained. Termination of the propagating species by ion-exchange or aminolysis with triethylamine yielded hydroxyl and quaternary ammonium terminated macromonomers, respectively.     

In vitro anti-mycobacterial activities of various 2'-deoxyuridine, 2'-arabinouridine and 2'-arabinofluoro-2'-deoxyuridine analogues: synthesis and biological studies

M. tuberculosis, M. bovis and M. avium infections cause the most important mycobacterioses leading to increased mortality in patients with AIDS. Various 5-substituted 2'-deoxyuridines, arabinouridines, arabinocytidines and 2'-arabinofluoro-2'-deoxyuridines were synthesized and evaluated for their in vitro inhibitory activity against M. bovis, M. tuberculosis and M. avium. 5-(C-1 Substituted)-2'-deoxyuridine derivatives emerged as potent inhibitors of M. avium (MIC50 = 1-10 microg/mL range); 5-(1-azidovinyl)-2'-deoxyuridine being the most active (MIC50 = 1-5 microg/mL range). The nature of C-5 substituents appeared to be a determinant of anti-mycobacterial activity.     

Lack of association between schizophrenia and the phospholipase-A(2) genes cPLA2 and sPLA2

The well-established role of genetic factors in the etiology of schizophrenia together with reports of allelic association with cPLA2, a phospholipase-A(2) gene, a reported increase of phospholipase-A(2) activity, and the phospholipase-A(2) hypothesis of Horrobin et al. [1995: Med Hypotheses 45:605-613] strongly support cPLA2 (PLA2G4A) and sPLA2 (PLA2G1B) as candidate genes for schizophrenia. In search for allelic association between these phospholipase-A(2) genes and schizophrenia, two samples of Chinese and European origins, in total 328 unrelated schizophrenic patients and their parents, were investigated using Falk and Rubinstein's haplotype relative risk method. Both genes showed marginally significant evidence for association in the total sample (P 相似文献   

Synthesis and polymerization of 2-cyano-2-methyltrimethylene carbonate

2-Cyano -methyltrimethylene carbonate (CMTC, 2 ) was synthesized starting from 2-methylacrolein (6), propionaldehyde (8) or 2-hydroxymethyl-2-methyl-1,3-propanediol (9). A key position in this synthesis is held by 2,2-bis(hydroxymethyl)propionitrile ( 3 ), which in a first step, is reacted — in conjunction with 2,2-dimethyl-1,3-propanediol ( 20 0) — with diphenyl carbonate ( 17 ) to result in a statistical copolycarbonate. Ring-closing depolymerization of this polymer, with a catalyst based on tin, yields in a second step the title monomer, CMTC (2), along with 2,2-dimethyltrimethylene carbonate (DTC, 1b ). Separation of the two monomers can be achieved by selective solubilization of the latter in toluene. Polymerization of CMTC is performed preferentially by using weak nucleophiles as initiators, such as Et₂AlOEt, Al(O-secBu)₃ or MgBu₂, since strong nucleophiles such as BuLi or ZnEt₂ tend to give side reactions with the cyano group. Copolymerization of CMTC with DTC results in statistical copolymers. With Et₂AlOEt as initiator copolymers with Bernoulli statistics are obtained, with a ratio of diads DTC/DTC : (DTC/CMTC + CMTC/DTC) : CMTC/CMTC equal to 1:2:1 for equimolar feed composition. With MgBu₂ as initiator and the same feed composition, a copolymer with the diad ratio 1:5:1 is obtained. Poly(CMTC) is a crystalline polymer with a melting point of 132.9°C and a glass transition temperature of 68.8 °C.     

ZFPM2/FOG2 and HEY2 genes analysis in nonsyndromic tricuspid atresia

Tricuspid atresia (TriAt), the third most common cyanotic congenital heart defect (CHD), consists of complete lack of tricuspid valve formation, with no connection between the right atrium and the right ventricle. To date, the genetic mechanism responsible of TriAt is still obscure. However, animal models have suggested a role of cardiogenic Zfpm2/Fog2 and Hey2 genes in the pathogenesis of TriAt. Therefore, we screened 40 individuals affected by nonsyndromic TriAt for ZFPM2/FOG2 and HEY2 gene mutations. No pathogenetic mutation has been identified, thus failing to demonstrate a major role of ZFPM2/FOG2 and HEY2 genes in the pathogenesis of human TriAt.     

Native and activated antithrombin inhibits TMPRSS2 activity and SARS-CoV-2 infection

Host cell proteases such as TMPRSS2 are critical determinants of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) tropism and pathogenesis. Here, we show that antithrombin (AT), an endogenous serine protease inhibitor regulating coagulation, is a broad-spectrum inhibitor of coronavirus infection. Molecular docking and enzyme activity assays demonstrate that AT binds and inhibits TMPRSS2, a serine protease that primes the Spike proteins of coronaviruses for subsequent fusion. Consequently, AT blocks entry driven by the Spikes of SARS-CoV, MERS-CoV, hCoV-229E, SARS-CoV-2 and its variants of concern including Omicron, and suppresses lung cell infection with genuine SARS-CoV-2. Thus, AT is an endogenous inhibitor of SARS-CoV-2 that may be involved in COVID-19 pathogenesis. We further demonstrate that activation of AT by anticoagulants, such as heparin or fondaparinux, increases the anti-TMPRSS2 and anti-SARS-CoV-2 activity of AT, suggesting that repurposing of native and activated AT for COVID-19 treatment should be explored.     

13C NMR spectroscopy of 2-formamido-2-methylpropyl acrylate and poly(2-formamido-2-methylpropyl acrylate)

The synthesis and characterization of 2-formamido-2-methylpropyl acrylate (FMPA) is reported. ¹³C NMR spectra of FMPA in CDCl₃, CD₃OD, DMSO-d₆, DMF-d₇, and D₂O exhibit two pairs of lines for all seven carbon atoms at room temperature; the ratio of the two conformers varies moderately with solvent (21 : 79 to 41 : 59). The conformers are believed to involve strong internal hydrogen bonding which is not completely broken even by the addition of trifluoroacetic acid to CDCl₃ (1/1, v/v). However, the pairs of lines coalesce in turn as the temperature is raised to 120°C in DMSO-d₆. FMPA was polymerized at 35°C in DMF and CHCl₃, using a free radical initiator and the polymer was characterized by ¹³C NMR spectroscopy.     

FoxC2与肿瘤

Fox(叉头框)是一个拥有相似的DNA结合域的蛋白家族,对DNA的转录起着至关重要的作用.目前研究发现这个蛋白家族在肿瘤的发生和发展的许多方面起着决定性的作用.而FOX家族成员FoxC2在肿瘤中的作用近年来也受到广泛的关注,本文对FoxC2在肿瘤血管生成、转移以及预后评估中的作用的研究进展进行综述.     

Kinesin-2 mediates physical and functional interactions between polycystin-2 and fibrocystin

Autosomal dominant polycystic kidney disease (ADPKD) is caused by mutations in PKD1, encoding polycystin-1 (PC1), or PKD2 (polycystin-2, PC2). Autosomal recessive PKD (ARPKD) is caused by mutations in PKHD1, encoding fibrocystin/polyductin (FPC). No molecular link between ADPKD and ARPKD has been determined. Here, we demonstrated, by yeast two-hybrid and biochemical assays, that KIF3B, a motor subunit of kinesin-2, associates with PC2 and FPC. Co-immunoprecipitation experiments using Madin-Darby canine kidney (MDCK) and inner medullary collecting duct (IMCD) cells and human kidney revealed that PC2 and KIF3B, FPC and KIF3B and, furthermore, PC2 and FPC are endogenously in the same complex(es), though no direct association between the PC2 and FPC intracellular termini was detected. In vitro binding and Far Western blot experiments demonstrated that PC2 and FPC are in the same complex only if KIF3B is present, presumably by forming a PC2-KIF3B-FPC complex. This was supported by our observation that altering KIF3B level in IMCD cells by over-expression or siRNA significantly affected complexing between PC2 and FPC. Immunofluorescence experiments showed that PC2, FPC and KIF3B partially co-localized in primary cilia of over-confluent and perinuclear regions of sub-confluent cells. Furthermore, KIF3B mediated functional modulation of purified PC2 channels by FPC in a planer lipid bilayer electrophysiology system. The FPC C-terminus substantially stimulated PC2 channel activity in the presence of KIF3B, whereas FPC or KIF3B alone had no effect. Taken together, we discovered that kinesin-2 is a linker between PC2 and FPC and mediates the regulation of PC2 channel function by FPC. Our study may be important for elucidating common molecular pathways for PKD of different genotypes.     

KIR2DL2/S2 and KIR2DS5 in alcoholic cirrhotic patients undergoing liver transplantation

IntroductionThe molecular mechanisms underlying alcoholic liver fibrosis and cirrhosis are not completely understood. Hepatic fibrosis involves the interplay of diverse cells and factors, including hepatic stellate cells (HSCs), Kupffer, NK cells, and T-lymphocyte subsets. Killer-cell immunoglobulin-like receptors (KIR) are membrane receptors involved in mediation between NK and activated HSCs, regulating NK cell function through their interaction with HLA-I molecules. The aim of this study was to analyse the genetic association between KIR genes and the susceptibility to or protection from alcoholic cirrhosis (AC) in a cohort of male AC patients undergoing liver transplantation (LT) with and without concomitant viral infections.Material and methodsKIR genotyping was performed in nuclear DNA extracted from 281 AC patients and compared with 319 male controls.ResultsSignificant differences between total AC patients and healthy controls were only found in the case of KIR2DL2 and KIR2DS5. KIR2DL2 was significantly underrepresented in non-viral AC patients (52.6% vs. 63.3%; p = 0.015), while patients heterozygous for KIR2DL2 were also underrepresented in the non-viral AC group compared with controls (p = 0.034). KIR2DS5 was overrepresented in this group compared with healthy controls (p = 0.002). All these observations were only evident in AC patients older than 54 years old.ConclusionsOur data suggest a contrary effect of KIR2DL2 and KIR2DS5 in AC patients older than 54 years, in whom the presence of KIR2DL2 appears to be protective against AC, whereas the presence of KIR2DS5 seems to promote the fibrotic process, particularly in patients with no associated viral infection.     

EphA2与肿瘤

酪氨酸蛋白激酶受体(receptor tyrosine kinases，RTKs)参与细胞增生和分化、胚胎发育和细胞内信号转导等过程，具有重要的生理功能。生促红素人肝细胞(erythropoietin-producing human hepatocelluar, Eph) A2 是Eph受体酪氨酸蛋白激酶家族RTKs中的一员，广泛表达在人类多种组织或细胞系中，对调节细胞生长、迁移及血管形成有潜在的作用。EphA2过表达可导致细胞的恶性转化，增强肿瘤细胞的侵袭性和转移性。EphA2有望成为恶性肿瘤治疗的新的靶点和预后指标。     

Neurofibromatosis 1 and 2

Neurofibromatosis (NF) 1 and 2 are multisystem disorders associated with a variety of neoplastic and non-neoplastic manifestations that typically progress in severity during the lifetime of the affected patient. The importance of appropriately diagnosing these disorders stems from the fact that the natural history of an associated neoplasm, such as a peripheral nerve tumor or an optic glioma, may be significantly different depending on whether or not the lesion arises in a person with NF. In addition, the indications for therapeutic intervention, hierarchy of treatment options and long-term management goals may differ substantially for patients with NF-related versus sporadic tumors. Finally, recognition of the diagnosis comprises an essential step for providing appropriate multidisciplinary evaluation and counseling to affected patients and their families. This article addresses the principal manifestations of these disorders and provides a contemporary review of the diagnostic and therapeutic issues that arise in children with NF1 and NF2.     

Isolation of a novel KIR2DL3-specific mAb: comparative analysis of the surface distribution and function of KIR2DL2, KIR2DL3 and KIR2DS2

In recent years an increasing number of sequences coding for new KIRs have been described. However, the limited availability of mAbs with unique KIR specificities has hindered an exhaustive assessment of their actual function, HLA-specificity, expression at the cell surface and distribution in different cell populations. In this study we report the generation of a novel mAb (ECM41) specific for KIR2DL3 molecules. By the use of cell transfectants expressing one or other KIR we show that this reagent allows discrimination of KIR2DL3 from other GL183 mAb-reactive molecules such as KIR2DL2 and KIR2DS2. Moreover we show that this novel mAb can be used to assess the surface expression and distribution of KIR2DL3 in different polyclonal NK populations and in NK cell clones. Along this line, we were able to analyze the HLA class I specificity of NK clones expressing either KIR2DL3 or KIR2DL2, two inhibitory receptors that were so far serologically undistinguishable. Finally, the combined use of GL183 and ECM41 mAbs in redirected killing assays allowed us to investigate the functional outcome of the simultaneous engagement of KIR2DL3 and KIR2DS2 in NK cell clones co-expressing KIRs that display opposite (inhibitory vs activating) function.     

EPR Identification of Zr(III) Complexes Formed upon Interaction of (2-PhInd)2ZrCl2 and rac-Me2Si(1-Ind)2ZrCl2 with MAO and MMAO

Reactions of 1 and 2 with MAO and MMAO were monitored by EPR. It was found that MMAO is a stronger reducing agent than MAO. 1 is more prone to reduction than 2 . The reduction of Zr^IV to Zr^III seems to be the essential pathway of some zirconocene catalysts' deactivation. Zr^III species with the following proposed structures can be identified in the 1 /MMAO system: (2-PhInd)₂Zr^III(ⁱBu), (2-PhInd)₂Zr^III(µ-Cl)₂AlⁱBu₂, (2-PhInd)₂Zr^III(µ-Cl)(ⁱBu)AlⁱBu₂, and [(2-PhInd)₂Zr^III]⁺[Me-MAO]⁻. The degree of reduction of Zr^IV species determined by EPR in the catalytic system 2 /MMAO can be masked by the formation of diamagnetic Zr^III/Zr^III dimers. Addition of monomers to the 2 /MAO system promotes reduction ot the zirconium species.

     

Cross-Protection in Mice After Immunization with H2N2, H3N2, and Heq2Neq2 Influenza Virus Strains

Mice were vaccinated with the influenza viruses A/Japan/57 (H2N2), A/Hong Kong/68 (H3N2), and A/Equi/Miami/63 (Heq2Neq2) and the hemagglutinin and neuraminidase recombinants derived from these viruses. After infection with the parent viruses, protection was compared with serological findings. It was found that influenza vaccine protects not only against infection with a strain identical or closely related to the vaccine strain, but against heterologous strains as well. Vaccination with Hong Kong/68 and its neuraminidase recombinant resulted in a heterologous neuraminidase inhibition titer against Japan/57 and in a protection against infection with Japan/57. By contrast, after vaccination with Japan/57 and its neuraminidase recombinant, no relevant heterologous neuraminidase inhibition titer against Hong Kong/68 was observed, whereas a protection against infection with Hong Kong/68 did exist. A cross-protection between Hong Kong/68 and Miami/63, but no relationship in the hemagglutination or neuraminidase inhibition tests, was established in the preinfection sera. A one-way antigenic relationship between these viruses was confirmed by the rise of hemagglutinin or neuraminidase antibodies against Hong Kong/68 in the postinfection sera. No cross-protection or serological relationship existed between Miami/63 and Japan/57. Besides the hemagglutinin and neuraminidase, a third factor, the “mouse-protecting antigen,” was considered to contribute to the protection obtained. According to the protection observed, the mouse-protecting antigen of Hong Kong/68 virus is related to that of Japan/57 as well as Miami/63 virus. The mouse-protecting antigens of both Japan/57 and Miami/63 are related to that of Hong Kong/68.