N-aryl-piperidine-4-carboxamides as a novel class of potent inhibitors of MALT1 proteolytic activity

Starting from a weak screening hit, potent and selective inhibitors of the MALT1 protease function were elaborated. Advanced compounds displayed high potency in biochemical and cellular assays. Compounds showed activity in a mechanistic Jurkat T cell activation assay as well as in the B-cell lymphoma line OCI-Ly3, which suggests potential use of MALT1 inhibitors in the treatment of autoimmune diseases as well as B-cell lymphomas with a dysregulated NF-κB pathway. Initially, rat pharmacokinetic properties of this compound series were dominated by very high clearance which could be linked to amide cleavage. Using a rat hepatocyte assay a good in vitro-in vivo correlation could be established which led to the identification of compounds with improved PK properties.     

Environmental determinants of genetic diversity in Caragana microphylla (Fabaceae) in northern China

Non‐rewarding orchids rely on various ruses to attract their pollinators. One of the most common is for them to resemble flowers sought by insects as food sources. This can range from generalized food deception to the mimicry of specific sympatric food plants. We investigated the basis of pollinator deception in the European food‐deceptive orchid Traunsteinera globosa, which has unusually compact flowerheads resembling those of sympatric rewarding species of Knautia and Scabiosa (Dipsacaceae), and Valeriana (Caprifoliaceae). Visual signals of T. globosa are similar in both fly and bee vision models to those of the sympatric food plants used in the choice experiments, but scent signals are divergent. Field experiments conducted in Austria and the Czech Republic showed that both naive and experienced (with respect to visitation of T. globosa) insect species approached the orchids at the same rate as food plants, but direct contact with orchid flowers was taxon specific. Flies were most easily duped into probing the orchid, and, in doing so, frequently received and deposited pollinaria, whereas most bees and butterflies avoided landing on orchid flowers. We conclude that T. globosa is a mimic of a guild of fly‐pollinated plants, but the ecological dependence of the orchid on its models remains to be fully tested. © 2015 The Linnean Society of London, Botanical Journal of the Linnean Society, 2016, 180 , 269–294.     

Genome-Wide Identification of Epigenetic Hotspots Potentially Related to Cardiovascular Risk in Adult Women after a Complicated Pregnancy

Background

The physiological demands of pregnancy on the maternal cardiovascular system can catapult women into a metabolic syndrome that predisposes to atherosclerosis in later life. We sought to identify the nature of the epigenomic changes associated with the increased cardiovascular disease (CVD) risk in adult women following pre-eclampsia.

Findings

We assessed the genome wide epigenetic profile by methyl-C sequencing of monozygotic parous twin sister pairs discordant for a severe variant of pre-eclampsia. In the adult twin sisters at risk for CVD as a consequence of a complicated pregnancy, a set of 12 differentially methylated regions with at least 50% difference in methylation percentage and the same directional change was found to be shared between the affected twin sisters and significantly different compared to their unaffected monozygous sisters.

Conclusion

The current epigenetic marker set will permit targeted analysis of differentially methylated regions potentially related to CVD risk in large cohorts of adult women following complicated pregnancies.     

Transactions of the One Hundredth Annual Meeting of The Canadian Medical Association: Part II

The purpose of this retrospective study was to compare (1) regular methadone withdrawal treatment and (2) prolonged methadone withdrawal treatment in 105 and 71 voluntary patients respectively, who attended the Narcotic Addiction Foundation (N.A.F.) between 1959 and mid-1964. Treatment consisted of individual counselling and medical care for all, and only residential care and psychiatric assessment for selected cases. The number of treatment sessions and the details of drug therapy are described.One hundred and fifty-three of 176 patients (87%) were interviewed approximately one to five years after the first clinic contact. Forty-three per cent showed some overall improvement in their behaviour. Rehabilitation was defined as change in a specific area—drug use, work, criminal behaviour, community associations, friendship patterns and family relationships—rather than in terms of abstention from drugs only. Age affected comparative results.     

Role of T-region borders in Agrobacterium host range

The limited host range AB3 strain of Agrobacterium tumefaciens induces tumors by transferring two T-regions, TA and TB. TA is a deleted version of the well-known biotype I octopine TL-region that lacks the iaa and ipt genes, but carries an intact oncogene, gene 6b, and typical left and right border sequences. TB carries two iaa genes that together code for the synthesis of indoleacetic acid. Gene 6b and the iaa gene act synergistically when transferred in a coinoculation experiment. The TA-region of the limited host range isolate Ag57 is related to the TA-region of AB3, but differs from it at several positions. The most significant difference is the absence of the right border region. In spite of this, Ag57 and the exconjugant strain C58C9(pTiAg57) induce normal tumors on Nicotiana rustica and Vitis vinifera. Various experiments indicate that gene 6b of the Ag57 TA-region is active and transferred in spite of the absence of the right border. On N. tabacum, C58C9(pTiAg57) is nononcogenic but becomes oncogenic when the pTiAg57 TA-region is restored by the right TA border sequence of pTiAB3. Thus, the right TA border sequence of the biotype III limited host range strains is required for tumor induction on some hosts, but not on others.     

Sequence of the iaa and ipt region of different Agrobacterium tumefaciens biotype III octopine strains: reconstruction of octopine Ti plasmid evolution

The TA regions of biotype III octopine/cucumopine (OC) Ti plasmids are closely related to the TL region of the biotype I octopine Ti plasmids pTiAch5 and pTi15955. Sequence analysis shows that the limited and wide host range biotype III OC TA regions are derived from a common ancestor structure which lacked the 6a gene found in the biotype I octopine TL region. The TA region of the wide host range OC Ti plasmids has conserved most of the original TL-like structure. In most wide host range OC isolates the TA-iaaH gene is inactivated by the insertion of an IS866 element. However, the TA region of the wide host range isolate Hm1 carries an intact TA-iaaH gene. This gene encodes a biologically active product, as shown by root induction tests and indole-3-acetic acid measurements.The limited host range OC Ti plasmids pTiAB3 and pTiAg57 have shorter TA regions which are derived from a wide host range TA region. The AB3 type arose by an IS868-mediated, internal TA region deletion which removed the iaa genes and part of the ipt gene and left a copy of IS868 at the position of the deleted fragment. The pTiAB3 iaa/ipt deletion was followed by insertion of a second IS element, IS869, immediately 3 of the ipt gene. pTiAg57 underwent the same iaa-ipt deletion as pTiAB3, but lacks the IS868 and IS869 elements.Analysis of the various TA region structures provides a detailed insight into the evolution of the biotype III OC strains.