Cholangiocytes in the pathogenesis of primary sclerosing cholangitis and development of cholangiocarcinoma

Primary sclerosing cholangitis (PSC) is an idiopathic cholangiopathy strongly associated with inflammatory bowel disease (IBD) and characterized by cholestasis, chronic immune infiltration and progressive fibrosis of the intrahepatic and extrahepatic bile ducts. PSC confers a high risk of cholangiocarcinoma (CCA) with PSC-CCA representing the leading cause of PSC-associated mortality. PSC-CCA is derived from cholangiocytes and associated progenitor cells – a heterogeneous group of dynamic epithelial cells lining the biliary tree that modulate the composition and volume of bile production by the liver. Infection, inflammation and cholestasis can trigger cholangiocyte activation leading to an increased expression of adhesion and antigen-presenting molecules as well as the release of various inflammatory and fibrogenic mediators. As a result, activated cholangiocytes engage in a myriad of cellular processes, including hepatocellular proliferation, apoptosis, angiogenesis and fibrosis. Cholangiocytes can also regulate the recruitment of immune cells, mesenchymal cells, and endothelial cells that participate in tissue repair and destruction in settings of persistent inflammation. In PSC, the role of cholangiocytes and the mechanisms governing their transformation to PSC-CCA are unclear however localization of disease suggests that cholangiocytes are a key target and potential regulator of hepatobiliary immunity, fibrogenesis and tumorigenesis. Herein, we summarize mechanisms of cholangiocyte activation in PSC and highlight new insights into disease pathways that may contribute to the development of PSC-CCA. This article is part of a Special Issue entitled: Cholangiocytes in Health and Disease edited by Jesus Banales, Marco Marzioni, Nicholas LaRusso and Peter Jansen.     

Bi-modal vertical distribution of the carnivorous copepod Paraeuchaeta norvegica

Bi-modal vertical distribution of Paraeuchaeta norvegica duringlate autumn was observed in a Norwegian fjord in three differentyears, and hence seems to be a recurring phenomenon. An uppermode performed diel vertical migration, foraging in shallowwater at night. A deep mode did not migrate vertically, butsome feeding took place at depth.     

Prevalence of skull pathologies in European harbor seals (<Emphasis Type="Italic">Phoca vitulina</Emphasis>) during 1981–2014

Harbor seals (Phoca vitulina) inhabit the seas surrounding Denmark and are an important top predator in the marine food chain. This trophic position exposes them to environmental contaminants with disease epidemics and hunting being additional threats to this population. It is therefore important to study how environmental pollution at the current order of magnitude affects the health of the population. Earlier studies have shown that occurrence of periodontitis could be linked to the amount of pollution the seals were subjected to. In order to investigate this further, 380 skulls and 141 mandibles of harbor seals (Phoca vitulina) from the Wadden Sea, the Limfjord, and Kattegat collected during the period 1970–2014 were examined. The skulls were examined for pathological lesions. The Hounsfield Units (HU) which are correlated to the bone mineral density (BMD) were measured in a subsample (n = 34) using CT scans. The macroscopic examination revealed (with the exception of the Swedish part of Kattegat) a significant increase of pathological lesions over the study period of 1981–2014. The examination of HU showed that median HU measured at multiple sites was highest in the healthy skulls compared to the skulls with one or more of the lesions. A discriminant analysis allowed high discriminatory capacity to separate healthy skulls from the skulls with pathologies, simply by the utilization of the HU data. Former studies of BMD in marine mammals have shown that exposure to environmental chemicals alter BMD and cause periodontitis. The present study, based on temporal and spatial trends in BMD, confirms the results of previous studies.     

Potent antibacterial lysine-peptoid hybrids identified from a positional scanning combinatorial library

In this paper, we describe the synthesis and screening of a biased positional scanning library made up of peptoids (N-alkylglycines) and lysines. The library consisted of 100 mixtures divided into four sub-libraries; OXXXKKK, XOXXKKK, XXOXKKK, and XXXOKKK, O being a defined peptoid building block and X a mixture of 25 peptoid building blocks. A theoretical number of 390,625 compounds were synthesized. The compound mixtures were screened against the American Type Culture Collection (ATCC) Staphylococcus aureus ATCC 25923 and Escherichia coli ATCC 25922 bacterial strains, and the cytotoxic activities were assessed using a human blood hemolytic assay. The results from each sub-library were examined to identify the most potent amine at each position. On the basis of this knowledge eight new lysine-peptoid hybrids were synthesized and tested in the biological assays. One compound in particular, [N-(cyclohexylmethyl)glycyl]-[N-(1-methylhexyl)glycyl]-[N-(4-methylbenzyl)glycyl]-[N-(2-(3-chlorophenyl)ethyl)glycyl]-lysyl-lysyl-lysine amide, showed high antibacterial activity and low toxicity toward red blood cells.     

Identification of 5-hydroxycytidine at position 2501 concludes characterization of modified nucleotides in E. coli 23S rRNA

Complete characterization of a biomolecule's chemical structure is crucial in the full understanding of the relations between their structure and function. The dominating components in ribosomes are ribosomal RNAs (rRNAs), and the entire rRNA—but a single modified nucleoside at position 2501 in 23S rRNA—has previously been characterized in the bacterium Escherichia coli. Despite a first report nearly 20 years ago, the chemical nature of the modification at position 2501 has remained elusive, and attempts to isolate it have so far been unsuccessful. We unambiguously identify this last unknown modification as 5-hydroxycytidine—a novel modification in RNA. Identification of 5-hydroxycytidine was completed by liquid chromatography under nonoxidizing conditions using a graphitized carbon stationary phase in combination with ion trap tandem mass spectrometry and by comparing the fragmentation behavior of the natural nucleoside with that of a chemically synthesized ditto. Furthermore, we show that 5-hydroxycytidine is also present in the equivalent position of 23S rRNA from the bacterium Deinococcus radiodurans. Given the unstable nature of 5-hydroxycytidine, this modification might be found in other RNAs when applying the proper analytical conditions as described here.     

Subdoligranulum variabile gen. nov., sp. nov. from human feces

During studies on the microflora of human feces we have isolated a strictly anaerobic, non-spore-forming, Gram-negative staining organism which exhibits a somewhat variable coccus-shaped morphology. Comparative 16S ribosomal RNA gene sequencing studies show the unidentified organism is phylogenetically a member of the Clostridium leptum supra-generic rRNA cluster and displays a close affinity to some rDNA clones derived from human and pig feces. The nearest named relatives of the unidentified isolate corresponded to Faecalibacterium prausnitzii (formerly Fusobacterium prausnitzii) displaying a 16S rRNA sequence divergence of approximately 9%, with Anaerofilum agile and A. pentosovorans the next closest relatives of the unidentified bacterium (sequence divergence approximately 10%). Based on phenotypic and phylogenetic considerations, it is proposed that the unusual coccoid-shaped organism be classified as a new genus and species, Subdoligranulum variabile. The type strain of S. variabile is BI 114(T) (=CCUG 47106(T)=DSM 15176(T)).     

Evolution of deceit by worthless donations in a nuptial gift-giving spider

Males of the nursery web spider Pisaura mirabil usually offer an insect prey wrapped in white silk as a nuptial gift to facilitate copulation. Males exploit female foraging preferences in a sexual context as females feed on the gift during copula- tion. It is possible for males to copulate without a gift, however strong female preference for the gift leads to dramatically higher mating success for gift-giving males. Females are polyandrous, and gift-giving males achieve higher mating success, longer copulations, and increased sperm transfer that confer advantages in sperm competition. Intriguingly, field studies show that ap- proximately one third of males carry a worthless gift consisting of dry and empty insect exoskeletons or plant fragments wrapped in white silk. Silk wrapping disguises gift content and females are able to disclose gift content only after accepting and feeding on the gift, meanwhile males succeed in transferring sperm. The evolution of deceit by worthless gift donation may be favoured by strong intra-sexual competition and costs of gift-construction including prey capture, lost foraging opportunities and investment in silk wrapping. Females that receive empty worthless gifts terminate copulation sooner, which reduces sperm transfer and likely disadvantages males in sperm competition. The gift-giving trait may thus become a target of sexually antagonistic co-evolution, where deceit by worthless gifts leads to female resistance to the trait. We discuss factors such as female mating rate and intensity of sperm competition that may shape the evolution of male deception, and how ecological factors may influence the evolution and maintenance of worthless gifts as an evolutionarily stable alternative mating strategy by frequency dependent selection     

Matrix Metalloproteinase 7 Is Associated with Symptomatic Lesions and Adverse Events in Patients with Carotid Atherosclerosis

Background

Atherosclerosis is a major cause of cerebrovascular disease. Matrix metalloproteinases (MMPs) play an important role in matrix degradation within the atherosclerotic lesion leading to plaque destabilization and ischemic stroke. We hypothesized that MMP-7 could be involved in this process.

Methods

Plasma levels of MMP-7 were measured in 182 consecutive patients with moderate (50–69%) or severe (≥70%) internal carotid artery stenosis, and in 23 healthy controls. The mRNA levels of MMP-7 were measured in atherosclerotic carotid plaques with different symptomatology, and based on its localization to macrophages, the in vitro regulation of MMP-7 in primary monocytes was examined.

Results

Our major findings were (i) Patients with carotid atherosclerosis had markedly increased plasma levels of MMP-7 compared to healthy controls, with particularly high levels in patients with recent symptoms (i.e., within the last 2 months). (ii) A similar pattern was found within carotid plaques with markedly higher mRNA levels of MMP-7 than in non-atherosclerotic vessels. Particularly high protein levels of MMP-7 levels were found in those with the most recent symptoms. (iii) Immunhistochemistry showed that MMP-7 was localized to macrophages, and in vitro studies in primary monocytes showed that the inflammatory cytokine tumor necrosis factor-α in combination with hypoxia and oxidized LDL markedly increased MMP-7 expression. (iv) During the follow-up of patients with carotid atherosclerosis, high plasma levels of MMP-7 were independently associated with total mortality.

Conclusion

Our findings suggest that MMP-7 could contribute to plaque instability in carotid atherosclerosis, potentially involving macrophage-related mechanisms.     

Infant SES as a Predictor of Personality—Is the Association Mediated by Intelligence?

Background

Although research into the continuity and change of personality traits during a lifespan has been fairly extensive, little research has been conducted on childhood predictors of adult personality.

Purpose

We aimed to investigate the association between infant socioeconomic status (SES), and Eysenck personality traits in adulthood. An additional aim was to investigate whether intelligence and education may mediate this association.

Methods

SES of 9125 children in the Copenhagen Perinatal Cohort was recorded at a 1-year examination. A subsample of this cohort, comprising 1182 individuals, participated in a follow-up at 20–34 years and was administered the Eysenck Personality Questionnaire (EPQ) which includes measures of neuroticism, extraversion, psychoticism and the so-called lie-scale. Associations of SES with each of the four personality traits were analysed by bivariate and partial correlations, and the mediating effects of intelligence and years of education were analysed.

Results

Higher SES in infancy was associated with lower neuroticism (r = −0.06; p = 0.05), lower lie-scale scores (r = −0.11; p = 0.0002), and higher psychoticism (r = 0.09; p = 0.003). However, analyses of mediation revealed no direct effect of infant SES on any of the adult personality traits, but only indirect effects mediated by intelligence and years of education, with intelligence being the main mediating factor.

Conclusion

Only weak associations were observed between infant SES and personality in young adulthood, and the observed associations were mediated by adult intelligence and educational level. Thus, factors associated with infant SES or family background appears to have weak direct effects on personality development.