Ubiquitin Binding in Endocytosis – How Tight Should It Be and Where Does It Happen?

Ubiquitin is an important tag in membrane transport. From studies in yeast, monoubiquitin has been considered sufficient to elicit uptake of cell surface transporters and receptors into endosomes. Two articles in the current issue of Traffic (Hawryluk et al. and Barriere et al.) indicate that stronger binding is required to retain and concentrate cargo in endocytic microdomains of the plasma membrane. High avidity interactions can be obtained by tandemly arrayed ubiquitin interaction motifs (UIM), in proteins such as the endocytic adaptors epsin and Eps15, interacting with polyubiquitin or by UIM-containing proteins binding several ubiquitins brought together through oligomerization of receptors. A controversial issue has been where such interactions take place. One view is that the association of epsin with ubiquitinated cargo is negatively regulated by its interaction with clathrin (Chen H and De Camilli P. Proc Natl Acad Sci USA 2005;102:2766-2771). This contention is now challenged by the articles of Hawryluk et al. and Barriere et al. Hawryluk et al. demonstrate that epsin and Eps15 consistently co-localize with clathrin but never with caveolin.     

Drivers of freshwater fish colonisations and extirpations under climate change

Climate change is expected to bring about profound rearrangement of ecological communities by affecting individual species distributions. The resulting communities arise from the idiosyncratic responses of species to future changes, which ultimately relate to both shrinking and expanding species ranges. While spatial patterns of colonisation and extirpation events have received great attention, the identification of specific drivers remains poorly explored. This study aims to investigate the relative contribution of species gain and loss to the turnover of fish assemblages in French rivers under future climate change, and to identify their principal drivers. Future projections of potential habitat suitability in 2080 derived from species distribution models for 40 fish species showed that colonisations and extirpations could play counterbalancing roles in the reshuffling of communities. Simultaneously, these two processes exhibited patchy spatial patterns, segregated along the longitudinal and altitudinal gradients, resulting in dramatic species turnover of ～ 60% of the current composition of species assemblages. Beyond the effect of topographic location, colonisations were found to be driven by temperature seasonality while extirpations were affected by modifications in both thermal and precipitation regimes. These results generate the possibility of developing ecosystem‐based management tools focused on the early identification of areas where particular species may be sensitive to climate changes. Disentangling the drivers of colonisation and extirpation processes provides ready‐to‐use information that may be easily integrated into conservation planning. This information could be used to identify potential hotspots of species gain and loss and to then compare these hotspots with newly favourable areas so as to consider their actual accessibility in order to facilitate future range shifts.     

Intake of Farmed Atlantic Salmon Fed Soybean Oil Increases Insulin Resistance and Hepatic Lipid Accumulation in Mice

Background

To ensure sustainable aquaculture, fish derived raw materials are replaced by vegetable ingredients. Fatty acid composition and contaminant status of farmed Atlantic salmon (Salmo salar L.) are affected by the use of plant ingredients and a spillover effect on consumers is thus expected. Here we aimed to compare the effects of intake of Atlantic salmon fed fish oil (FO) with intake of Atlantic salmon fed a high proportion of vegetable oils (VOs) on development of insulin resistance and obesity in mice.

Methodology/principal findings

Atlantic salmon were fed diets where FO was partly (80%) replaced with three different VOs; rapeseed oil (RO), olive oil (OO) or soy bean oil (SO). Fillets from Atlantic salmon were subsequently used to prepare Western diets (WD) for a mouse feeding trial. Partial replacement of FO with VOs reduced the levels of polychlorinated biphenyls (PCB) and dichloro-diphenyl-tricloroethanes (DDT) with more than 50% in salmon fillets, in WDs containing the fillets, and in white adipose tissue from mice consuming the WDs. Replacement with VOs, SO in particular, lowered the n−3 polyunsaturated fatty acid (PUFA) content and increased n−6 PUFA levels in the salmon fillets, in the prepared WDs, and in red blood cells collected from mice consuming the WDs. Replacing FO with VO did not influence obesity development in the mice, but replacement of FO with RO improved glucose tolerance. Compared with WD-FO fed mice, feeding mice WD-SO containing lower PCB and DDT levels but high levels of linoleic acid (LA), exaggerated insulin resistance and increased accumulation of fat in the liver.

Conclusion/Significance

Replacement of FO with VOs in aqua feed for farmed salmon had markedly different spillover effects on metabolism in mice. Our results suggest that the content of LA in VOs may be a matter of concern that warrants further investigation.     

Mutations in Calmodulin Cause Ventricular Tachycardia and Sudden Cardiac Death

Catecholaminergic polymorphic ventricular tachycardia (CPVT) is a devastating inherited disorder characterized by episodic syncope and/or sudden cardiac arrest during exercise or acute emotion in individuals without structural cardiac abnormalities. Although rare, CPVT is suspected to cause a substantial part of sudden cardiac deaths in young individuals. Mutations in RYR2, encoding the cardiac sarcoplasmic calcium channel, have been identified as causative in approximately half of all dominantly inherited CPVT cases. Applying a genome-wide linkage analysis in a large Swedish family with a severe dominantly inherited form of CPVT-like arrhythmias, we mapped the disease locus to chromosome 14q31-32. Sequencing CALM1 encoding calmodulin revealed a heterozygous missense mutation (c.161A>T [p.Asn53Ile]) segregating with the disease. A second, de novo, missense mutation (c.293A>G [p.Asn97Ser]) was subsequently identified in an individual of Iraqi origin; this individual was diagnosed with CPVT from a screening of 61 arrhythmia samples with no identified RYR2 mutations. Both CALM1 substitutions demonstrated compromised calcium binding, and p.Asn97Ser displayed an aberrant interaction with the RYR2 calmodulin-binding-domain peptide at low calcium concentrations. We conclude that calmodulin mutations can cause severe cardiac arrhythmia and that the calmodulin genes are candidates for genetic screening of individual cases and families with idiopathic ventricular tachycardia and unexplained sudden cardiac death.     

The role of B cell CD22 expression in Staphylococcus aureus arthritis and sepsis

Severe Staphylococcus aureus infections give rise to a pronounced antigen-specific and polyclonal B cell response with elevated serum immunoglobulin levels. However, it has been difficult to correlate the antibody levels with the clinical outcome of sepsis and/or arthritis concerning both protection and pathogenic aspects. Earlier studies have shown that macrophages and neutrophils are of great importance for bacterial clearance. However, deletion of the complete B cell compartment affected neither S. aureus-induced arthritis nor survival. MZ B cells are believed to be of importance for clearance of blood-borne antigens and have been implicated in protection against S. aureus infections. CD22 is a B-cell-specific inhibitory receptor binding to alpha2,6-linked sialic acids, and deficiency in CD22 leads to a 75% reduction of the MZ B cell compartment. CD22-/- mice and congeneic controls were inoculated intravenously with an arthritogenic dose of live S. aureus. No differences between the groups were detected regarding frequency and severity of arthritis, survival, bacterial clearance, or induction of inflammatory response. This study shows explicitly that a reduced MZ B cell compartment in the absence of CD22 expression does not interfere with the inflammatory response during S. aureus infection.     

Overexpression of Glutathione Synthetase in Indian Mustard Enhances Cadmium Accumulation and Tolerance

An important pathway by which plants detoxify heavy metals is through sequestration with heavy-metal-binding peptides called phytochelatins or their precursor, glutathione. To identify limiting factors for heavy-metal accumulation and tolerance, and to develop transgenic plants with an increased capacity to accumulate and/or tolerate heavy metals, the Escherichia coli gshII gene encoding glutathione synthetase (GS) was overexpressed in the cytosol of Indian mustard (Brassica juncea). The transgenic GS plants accumulated significantly more Cd than the wild type: shoot Cd concentrations were up to 25% higher and total Cd accumulation per shoot was up to 3-fold higher. Moreover, the GS plants showed enhanced tolerance to Cd at both the seedling and mature-plant stages. Cd accumulation and tolerance were correlated with the gshII expression level. Cd-treated GS plants had higher concentrations of glutathione, phytochelatin, thiol, S, and Ca than wild-type plants. We conclude that in the presence of Cd, the GS enzyme is rate limiting for the biosynthesis of glutathione and phytochelatins, and that overexpression of GS offers a promising strategy for the production of plants with superior heavy-metal phytoremediation capacity.     

Comparative Genome Analysis Provides Insights into the Pathogenicity of Flavobacterium psychrophilum

Flavobacterium psychrophilum is a fish pathogen in salmonid aquaculture worldwide that causes cold water disease (CWD) and rainbow trout fry syndrome (RTFS). Comparative genome analyses of 11 F. psychrophilum isolates representing temporally and geographically distant populations were used to describe the F. psychrophilum pan-genome and to examine virulence factors, prophages, CRISPR arrays, and genomic islands present in the genomes. Analysis of the genomic DNA sequences were complemented with selected phenotypic characteristics of the strains. The pan genome analysis showed that F. psychrophilum could hold at least 3373 genes, while the core genome contained 1743 genes. On average, 67 new genes were detected for every new genome added to the analysis, indicating that F. psychrophilum possesses an open pan genome. The putative virulence factors were equally distributed among isolates, independent of geographic location, year of isolation and source of isolates. Only one prophage-related sequence was found which corresponded to the previously described prophage 6H, and appeared in 5 out of 11 isolates. CRISPR array analysis revealed two different loci with dissimilar spacer content, which only matched one sequence in the database, the temperate bacteriophage 6H. Genomic Islands (GIs) were identified in F. psychrophilum isolates 950106-1/1 and CSF 259–93, associated with toxins and antibiotic resistance. Finally, phenotypic characterization revealed a high degree of similarity among the strains with respect to biofilm formation and secretion of extracellular enzymes. Global scale dispersion of virulence factors in the genomes and the abilities for biofilm formation, hemolytic activity and secretion of extracellular enzymes among the strains suggested that F. psychrophilum isolates have a similar mode of action on adhesion, colonization and destruction of fish tissues across large spatial and temporal scales of occurrence. Overall, the genomic characterization and phenotypic properties may provide new insights to the mechanisms of pathogenicity in F. psychrophilum.     

Novel cyanoguanidines with potent oral antitumour activity

4-Pyridyl cyanoguanidines with hydrophobic aromatic side chains showed potent antiproliferative activity in the human breast and lung cancer cell lines MCF-7, NYH and H460. In vivo, treatment with N-(6-chlorophenoxyhexyl)-N′-cyano-N″-4-pyridylguanidine (18, 20 mg/kg/day po.), gave a complete remission of tumours in a model of NYH inoculated nude mice.     

Temperature and precipitation at migratory grounds influence demographic trends of an Arctic‐breeding bird

Anthropogenic climate disruption, including temperature and precipitation regime shifts, has been linked to animal population declines since the mid‐20th century. However, some species, such as Arctic‐breeding geese, have thrived during this period. An increased understanding of how climate disruption might link to demographic rates in thriving species is an important perspective in quantifying the impact of anthropogenic climate disruption on the global state of nature. The Greenland barnacle goose (Branta leucopsis) population has increased tenfold in abundance since the mid‐20th century. A concurrent weather regime shift towards warmer, wetter conditions occurred throughout its range in Greenland (breeding), Ireland and Scotland (wintering) and Iceland (spring and autumn staging). The aim of this study was to determine the relationship between weather and demographic rates of Greenland barnacle geese to discern the role of climate shifts in the population trend. We quantified the relationship between temperature and precipitation and Greenland barnacle goose survival and productivity over a 50 year period from 1968 to 2018. We detected significant positive relationships between warmer, wetter conditions on the Icelandic spring staging grounds and survival. We also detected contrasting relationships between warmer, wetter conditions during autumn staging and survival and productivity, with warm, dry conditions being the most favourable for productivity. Survival increased in the latter part of the study period, supporting the possibility that spring weather regime shifts contributed to the increasing population trend. This may be related to improved forage resources, as warming air temperatures have been shown to improve survival rates in several other Arctic and northern terrestrial herbivorous species through indirect bottom‐up effects on forage availability.