Microenvironment-derived IL-1 and IL-17 interact in the control of lung metastasis

Inflammatory cytokines modulate immune responses in the tumor microenvironment during progression/metastasis. In this study, we have assessed the role of IL-1 and IL-17 in the control of antitumor immunity versus progression in a model of experimental lung metastasis, using 3LL and B16 epithelial tumor cells. The absence of IL-1 signaling or its excess in the lung microenvironment (in IL-1β and IL-1R antagonist knockout [KO] mice, respectively) resulted in a poor prognosis and reduced T cell activity, compared with WT mice. In IL-1β KO mice, enhanced T regulatory cell development/function, due to a favorable in situ cytokine network and impairment in APC maturation, resulted in suppressed antitumor immunity, whereas in IL-1R antagonist KO mice, enhanced accumulation and activity of myeloid-derived suppressor cells were found. Reduced tumor progression along with improved T cell function was found in IL-17 KO mice, compared with WT mice. In the microenvironment of lung tumors, IL-1 induces IL-17 through recruitment of γ/δ T cells and their activation for IL-17 production, with no involvement of Th17 cells. These interactions were specific to the microenvironment of lung tumors, as in intrafootpad tumors in IL-1/IL-17 KO mice, different patterns of invasiveness were observed and no IL-17 could be locally detected. The results highlight the critical and unique role of IL-1, and cytokines induced by it such as IL-17, in determining the balance between inflammation and antitumor immunity in specific tumor microenvironments. Also, we suggest that intervention in IL-1/IL-17 production could be therapeutically used to tilt this balance toward enhanced antitumor immunity.     

The structure of the Lingo-1 ectodomain, a module implicated in central nervous system repair inhibition

Nogo receptor (NgR)-mediated control of axon growth relies on the central nervous system-specific type I transmembrane protein Lingo-1. Interactions between Lingo-1 and NgR, along with a complementary co-receptor, result in neurite and axonal collapse. In addition, the inhibitory role of Lingo-1 is particularly important in regulation of oligodendrocyte differentiation and myelination, suggesting that pharmacological modulation of Lingo-1 function could be a novel approach for nerve repair and remyelination therapies. Here we report on the crystal structure of the ligand-binding ectodomain of human Lingo-1 and show it has a bimodular, kinked structure composed of leucine-rich repeat (LRR) and immunoglobulin (Ig)-like modules. The structure, together with biophysical analysis of its solution properties, reveals that in the crystals and in solution Lingo-1 persistently associates with itself to form a stable tetramer and that it is its LRR-Ig-composite fold that drives such assembly. Specifically, in the crystal structure protomers of Lingo-1 associate in a ring-shaped tetramer, with each LRR domain filling an open cleft in an adjacent protomer. The tetramer buries a large surface area (9,200 A2) and may serve as an efficient scaffold to simultaneously bind and assemble the NgR complex components during activation on a membrane. Potential functional binding sites that can be identified on the ectodomain surface, including the site of self-recognition, suggest a model for protein assembly on the membrane.     

The ram1 Mutant of Arabidopsis Exhibits Severely Decreased β-Amylase Activity

Despite extensive biochemical analyses, the biological function(s) of plant β-amylases remains unclear. The fact that β-amylases degrade starch in vitro suggests that they may play a role in starch metabolism in vivo. β-Amylases have also been suggested to prevent the accumulation of highly polymerized polysaccharides that might otherwise impede flux through phloem sieve pores. The identification and characterization of a mutant of Arabidopsis var. Columbia with greatly reduced levels of β-amylase activity is reported here. The reduced β-amylase 1 (ram1) mutation lies in the gene encoding the major form of β-amylase in Arabidopsis. Although the Arabidopsis genome contains nine known or putative β-amylase genes, the fact that the ram1 mutation results in almost complete loss of β-amylase activity in rosette leaves and inflorescences (stems) indicates that the gene affected by the ram1 mutation is responsible for most of the β-amylase activity present in these tissues. The leaves of ram1 plants accumulate wild-type levels of starch, soluble sugars, anthocyanin, and chlorophyll. Plants carrying the ram1 mutation also exhibit wild-type rates of phloem exudation and of overall growth. These results suggest that little to no β-amylase activity is required to maintain normal starch levels, rates of phloem exudation, and overall plant growth.     

Sustained release varnish containing chlorhexidine for prevention of Streptococcus mutans biofilm formation on voice prosthesis surface: an in vitro study

International Microbiology - In this study, we aimed to develop a novel, sustained release varnish (SRV) for voice prostheses (VP) releasing chlorhexidine (CHX), for the prevention of biofilm...     

Proenkephalin and risk of developing chronic kidney disease: the Prevention of Renal and Vascular End-stage Disease study

Background: Proenkephalin (pro-ENK) was recently found to be associated with low estimated glomerular filtration rate (eGFR). The association of pro-ENK with urinary albumin excretion (UAE), another marker for chronic kidney disease (CKD), has not been investigated. We examined the association of pro-ENK with eGFR and UAE as markers of CKD.

Methods: We included 4375 subjects of the Prevention of Renal and Vascular End-Stage Disease (PREVEND) study. CKD_eGFR was defined as development of eGFR?<60?ml/min/1.73 m² and CKD_UAE as albuminuria?>30?mg/24?h.

Results: Baseline median pro-ENK was 52.2 (IQR: 44.9–60.5) pmol/L. After a median follow-up of 8.4 (IQR: 7.9–8.9) years, 183 subjects developed CKD_eGFR and 371 developed CKD_UAE. The association of pro-ENK with CKD_eGFR was modified by sex (P_interaction?SD increase in ¹⁰log-transformed pro-ENK, 1.65; 95% CI: 1.15–2.36) and not in women (0.83; 0.58–1.20). No significant association was observed between pro-ENK and CKD_UAE risk (0.83; 0.58–1.20).

Conclusions: High pro-ENK is associated with increased risk of CKD_eGFR in men, but not in women. No association of pro-ENK with CKD_UAE was observed. These results should be interpreted with caution, since residual confounding and potential overfitting of models could have influenced the results.     

Population structure,biometrics and moult of migrant Purple Sandpipers Calidris maritima in southwest Iceland in spring

Capsule Iceland is a stop‐over site for a population of Purple Sandpipers that winter in Britain. Here, they accumulate fuel loads for onward migration along with birds that have wintered in Iceland.

Aims To establish whether Purple Sandpipers from Britain stop‐over in Iceland during spring migration and, if so, to describe their population structure, changes in mass and moult.

Methods Purple Sandpipers were cannon‐netted on the coast of the Reykjanes Peninsula in southwest Iceland during May 2003 and 2005. Birds were aged, sexed (some by DNA) and standard biometric measurements made. Active body moult was scored.

Results Bill and wing lengths showed that the Purple Sandpipers we caught were similar to one of the populations that winter in Britain rather than Icelandic breeding birds. There were more males than females throughout the migration period (63% males for first‐year‐birds and 67% for adult birds). Accounting for a bias due to a higher percentage of males in a less usual habitat (muddy/sandy bays), the values for rocky sites were 52% males for first‐year birds and 62% for adults. The percentage of first‐year birds was 19% in 2003 and 32% in 2005, though the latter figure was biased by catches in muddy/sandy bays where there was a higher percentage of young birds. The percentage of first‐year birds was 25% on just the rocky shores in 2005. Many birds were in latter stages of body moult, and males were slightly in advance of females. Increasing mass showed that they were preparing for onward migration. The average increase of 0.58 g per day was similar to the rate measured in Orkney at an earlier point on the migration route. However, a high turnover of birds could be the reason for these low values. By late May, and close to the assumed departure date, the Purple Sandpipers of the different age/sex classes had fuel indices of 24–29% (33–42% of the lean mass). This was lower than that for the high Arctic sandpipers (Knots and Sanderlings) leaving southwest Iceland for Greenland and Canada.

Conclusions Our study confirmed that Purple Sandpipers do stop‐over in Iceland, and the possible lower rate of fuel accumulation and smaller amount stored, compared with Knots and Sanderlings, suggests a different migration pattern.