A note on suxamethonium sensitivity and serum cholinesterase variants

Summary Sera from 21 cases of prolonged apnoea which showed normal phenotype (UU) on the basis of dibucaine and fluoride inhibition were re-examined by replacing the substrate benzoylcholine with succinylcholine (suxamethonium). 9 samples had normal enzyme activity but low dibucaine number (DN=<20) indicating the atypical variant; 6 sera showed no detectable enzyme activity. The remaining 6 samples had enzyme activity and DN comparable with healthy controls. The occurence of new variants of serum cholinesterase sensitive only to succinylcholine is suggested.Dedicated to Prof. Dr. med. J. Kühnau on his 75th birthday.     

Ubiquitin‐Activated Interaction Traps (UBAITs) identify E3 ligase binding partners

We describe a new class of reagents for identifying substrates, adaptors, and regulators of HECT and RING E3s. UBAITs (Ub iquitin‐A ctivated I nteraction T raps) are E3‐ubiquitin fusion proteins and, in an E1‐ and E2‐dependent manner, the C‐terminal ubiquitin moiety forms an amide linkage to proteins that interact with the E3, enabling covalent co‐purification of the E3 with partner proteins. We designed UBAITs for both HECT (Rsp5, Itch) and RING (Psh1, RNF126, RNF168) E3s. For HECT E3s, trapping of interacting proteins occurred in vitro either through an E3 thioester‐linked lariat intermediate or through an E2 thioester intermediate, and both WT and active‐site mutant UBAITs trapped known interacting proteins in yeast and human cells. Yeast Psh1 and human RNF126 and RNF168 UBAITs also trapped known interacting proteins when expressed in cells. Human RNF168 is a key mediator of ubiquitin signaling that promotes DNA double‐strand break repair. Using the RNF168 UBAIT, we identify H2AZ—a histone protein involved in DNA repair—as a new target of this E3 ligase. These results demonstrate that UBAITs represent powerful tools for profiling a wide range of ubiquitin ligases.     

Antimutagenic and antitumorigenic activities of nordihydroguaiaretic acid.

Nordihydroguaiaretic acid (NDGA), which occurs in the resinous exudates of many plants is used as an antioxidant in fats and oils. In this study we show that NDGA inhibited the mutagenicity of methyl methanesulfonate, benzo[a]pyrene (BP), 2-aminofluorene, and aflatoxin B1 in Salmonella typhimurium strain TA100 or TA98 in the absence and presence of rat hepatic microsomal activation system. The addition of NDGA during and after nitrosation of methylurea (MU) resulted in a dose-dependent inhibition of mutagenicity induced by nitrosation products of MU. In a two-stage skin tumorigenesis protocol using 7,12-dimethylbenz[a]anthracene (DMBA) as the initiating agent followed by twice weekly applications of 12-O-tetradecanoylphorbol-13-acetate (TPA) as tumor promoter, pretreatment of animals with NDGA prior to DMBA application, afforded significant protection against skin tumorigenicity in female SENCAR mice. In additional studies, skin application of NDGA also inhibited the binding of topically applied [3H]BP and [3H]DMBA to epidermal DNA. When assessed in the anti-tumor promotion protocol, pretreatment of animals with NDGA before each application of TPA in DMBA-initiated mouse skin, resulted in 72% decrease in the total number of tumors when compared to non-NDGA pretreated animals. The possible mechanism(s) of the antimutagenic and anti-tumorigenic activities may be due to the multiple effects of NDGA as inhibitor of the carcinogen metabolism and DNA-adduct formation, scavenger of carcinogen free radicals, and as inhibitor of TPA-induced ornithine decarboxylase activity.     

Neotropical Monogenoidea. 33. Three new species of Ancistrohaptor n. g. (Dactylogyridae,Ancyrocephalinae) on Triportheus spp. (Teleostei,Characidae) from Brazil,with checklists of ancyrocephalines recorded from neotropical characiform fishes

Three new species of Ancistrohaptor n. g. are described from the gills of three species of Triportheus (Characidae) collected from the environs of Manaus, Amazonas, Brazil: A. falcatum n. sp. from T. elongatus; and A. falciferum n. sp. and A. falcunculum n. sp. from T. angulatus, T. albus and T. elongatus. Ancistrohaptor n. g. is proposed for species possessing overlapping gonads, a dextral or dextroventral vaginal aperture, a coiled (counter-clockwise) male copulatory organ, two accessory pieces in the copulatory complex, and a haptor armed with two pairs of anchors (ventral anchor with elongate shaft), dorsal and ventral bars and 14 hooks; hook pair 1 (ventral) anterior to ventral bar, pairs 2–4 (ventral) lying bilaterally anterior to ventral anchor bases, pair 5 (ventral) associated with distal end of ventral anchor shafts, and pairs 6 and 7 (dorsal) bilateral about midway along haptoral length. Parasite-host and host-parasite lists of the Ancyrocephalinae from neotropical Characiformes are provided.     

Fungi causing plant diseases at jabalpur (madhya pradesh)-IX

Summary The present paper describes 6 foliicolous fungi from Jabalpur (India). These includeAsterina lawsoniae Syd. on leaves ofLawsonia alba, Diplocarpon rosae Wolf. onRosa sp.,Cercospora jujubae Chowdhury onZizyphus jujuba andCercospora subsessilis Henn. &Nym. onAzadirachta indica, new fungus records for Madhya Pradesh;Asterostomella strophanti Henn. on leaves ofFlacourtia ramontchii, a new fungus for the country andCorynespora cassiicola (Berk. &Curt.)Wei. onClerodendron inerme, a new host record.     

Na+/K+-ATPase is present in scrapie-associated fibrils, modulates PrP misfolding in vitro and links PrP function and dysfunction

Transmissible spongiform encephalopathies are characterised by widespread deposition of fibrillar and/or plaque-like forms of the prion protein. These aggregated forms are produced by misfolding of the normal prion protein, PrP(C), to the disease-associated form, PrP(Sc), through mechanisms that remain elusive but which require either direct or indirect interaction between PrP(C) and PrP(Sc) isoforms. A wealth of evidence implicates other non-PrP molecules as active participants in the misfolding process, to catalyse and direct the conformational conversion of PrP(C) or to provide a scaffold ensuring correct alignment of PrP(C) and PrP(Sc) during conversion. Such molecules may be specific to different scrapie strains to facilitate differential prion protein misfolding. Since molecular cofactors may become integrated into the growing protein fibril during prion conversion, we have investigated the proteins contained in prion disease-specific deposits by shotgun proteomics of scrapie-associated fibrils (SAF) from mice infected with 3 different strains of mouse-passaged scrapie. Concomitant use of negative control preparations allowed us to identify and discount proteins that are enriched non-specifically by the SAF isolation protocol. We found several proteins that co-purified specifically with SAF from infected brains but none of these were reproducibly and demonstrably specific for particular scrapie strains. The α-chain of Na(+)/K(+)-ATPase was common to SAF from all 3 strains and we tested the ability of this protein to modulate in vitro misfolding of recombinant PrP. Na(+)/K(+)-ATPase enhanced the efficiency of disease-specific conversion of recombinant PrP suggesting that it may act as a molecular cofactor. Consistent with previous results, the same protein inhibited fibrillisation kinetics of recombinant PrP. Since functional interactions between PrP(C) and Na(+)/K(+)-ATPase have previously been reported in astrocytes, our data highlight this molecule as a key link between PrP function, dysfunction and misfolding.     

Contrasting Roles of Islet Resident Immunoregulatory Macrophages and Dendritic Cells in Experimental Autoimmune Type 1 Diabetes

The innate immune system critically shapes diabetogenic adaptive immunity during type 1 diabetes (T1D) pathogenesis. While the role of tissue-infiltrating monocyte-derived macrophages in T1D is well established, the role of their tissue-resident counterparts remains undefined. We now demonstrate that islet resident macrophages (IRMs) from non-autoimmune mice have an immunoregulatory phenotype and powerfully induce FoxP3+ Tregs in vitro. The immunoregulatory phenotype and function of IRMs is compromised by TLR4 activation in vitro. Moreover, as T1D approaches in NOD mice, the immunoregulatory phenotype of IRMs is diminished as is their relative abundance compared to immunostimulatory DCs. Our findings suggest that maintenance of IRM abundance and their immunoregulatory phenotype may constitute a novel therapeutic strategy to prevent and/or cure T1D.