Imaging Mass Spectrometry Reveals Alterations in N-Linked Glycosylation That Are Associated With Histopathological Changes in Nonalcoholic Steatohepatitis in Mouse and Human

Nonalcoholic steatohepatitis (NASH) is the progressive form of nonalcoholic fatty liver disease (NAFLD) and is characterized by inflammation, hepatocyte injury, and fibrosis. Further, NASH is a risk factor for cirrhosis and hepatocellular carcinoma. Previous research demonstrated that serum N-glycan profiles can be altered in NASH patients. Here, we hypothesized that these N-glycan modifications may be associated with specific liver damage in NAFLD and NASH. To investigate the N-glycome profile in tissue, imaging mass spectrometry was used for a qualitative and quantitative in situ N-linked glycan analysis of mouse and human NAFLD/NASH tissue. A murine model was used to induce NAFLD and NASH through ad libitum feeding with either a high-fat diet or a Western diet, respectively. Mice fed a high-fat diet or Western diet developed inflammation, steatosis, and fibrosis, consistent with NAFLD/NASH phenotypes. Induction of NAFLD/NASH for 18 months using high caloric diets resulted in increased expression of mannose, complex/fucosylated, and hybrid N-glycan structures compared to control mouse livers. To validate the animal results, liver biopsy specimens from 51 human NAFLD/NASH patients representing the full range of NASH Clinical Research Network fibrosis stages were analyzed. Importantly, the same glycan alterations observed in mouse models were observed in human NASH biopsies and correlated with the degree of fibrosis. In addition, spatial glycan alterations were localized specifically to histopathological changes in tissue like fibrotic and fatty areas. We demonstrate that the use of standard staining’s combined with imaging mass spectrometry provide a full profile of the origin of N-glycan modifications within the tissue. These results indicate that the spatial distribution of abundances of released N-glycans correlate with regions of tissue steatosis associated with NAFLD/NASH.     

Synthesis of (Dicarbonyl)(η5-cyclopentadieny1)iron -Derived Nucleoside Phosphonate Esters

Abstract

New methods for generating phosphonate linkages in oligonucleotides are under investigation. Among reagents that react selectively with phosphite triesters and H-phosphonates are (dicarbonyl)(η⁵-cyclopentadienyl)(η²-olefin)iron complexes. We have found that (dicarbonyl)(η⁵-cyclopentadienyl)(η²-ethylene)iron reacts with 5′-O-dimethoxytritylnucleoside 3′-phosphite esters to yield (dicarbonyl)(η⁵-cyclopentadienyl)iron(ethyl)phosphonates. The (dicarbonyl)(η⁵-cyclopentadienyl)iron-derived nucleoside phosphonates are stable to the conditions commonly used to construct oligonucleotides by phosphoramidite methodology.     

The Coyote and the Sequential Occupants of the Los Angeles Basin

This study traces how the coyote (Canis latrans) has interacted with the differing culture groups which sequentially occupied the Los Angeles basin. The coyote's relationships with the aboriginal, the Spaniard, and the early American are compared, as well as the variance in which it was perceived by each group. Since the coyote survived urbanization to become the major predator within the Los Angeles basin, the present attitudes of urban dwellers toward the animal are also briefly assessed. The coyote's capacity to survive is being aided by an increasing public awareness of the aesthetic value of wild nature, thus its survival within one of North America's largest urban areas is relatively assured .     

The Response of the Tidepool Sculpin,Oligocottus maculosus,to Chemical Stimuli from Injured Conspecifics,Alarm Signalling in the Cottidae (Pisces)

The tidepool sculpin, Oligocottus maculosus, a small, cottiid fish of the Pacific coast of North America, shows reduced movement, less feeding activity, a greater tendency to attach itself to the substrate, and a shift from exposed areas to shelters and crevices when presented with water that has contained injured conspecifics. This alarm reaction does not occur in response to water that has contained uninjured, but disturbed, O. maculosus, or injured guppies, Poecilia reticulata, O. maculosus are not toxic or distasteful to piscine predators. They do possess large, epidermal sacciform cells that may contain the active chemical(s) released by injured individuals. This is the first report of chemical alarm signalling in Cottidae.