Small leucine rich proteoglycan family regulates multiple signalling pathways in neural development and maintenance

The small leucine-rich repeat proteoglycan (SLRPs) family of proteins currently consists of five classes, based on their structural composition and chromosomal location. As biologically active components of the extracellular matrix (ECM), SLRPs were known to bind to various collagens, having a role in regulating fibril assembly, organization and degradation. More recently, as a function of their diverse proteins cores and glycosaminoglycan side chains, SLRPs have been shown to be able to bind various cell surface receptors, growth factors, cytokines and other ECM components resulting in the ability to influence various cellular functions. Their involvement in several signaling pathways such as Wnt, transforming growth factor-β and epidermal growth factor receptor also highlights their role as matricellular proteins. SLRP family members are expressed during neural development and in adult neural tissues, including ocular tissues. This review focuses on describing SLRP family members involvement in neural development with a brief summary of their role in non-neural ocular tissues and in response to neural injury.

Proteomic analysis of coronary sinus serum reveals leucine-rich α2-glycoprotein as a novel biomarker of ventricular dysfunction and heart failure

BACKGROUND: Heart failure (HF) prevention strategies require biomarkers that identify disease manifestation. Increases in B-type natriuretic peptide (BNP) correlate with increased risk of cardiovascular events and HF development. We hypothesize that coronary sinus serum from a high BNP hypertensive population reflects an active pathological process and can be used for biomarker exploration. Our aim was to discover differentially expressed disease-associated proteins that identify patients with ventricular dysfunction and HF.

METHODS AND RESULTS: Coronary sinus serum from 11 asymptomatic, hypertensive patients underwent quantitative differential protein expression analysis by 2-dimensional difference gel electrophoresis. Proteins were identified using mass spectrometry and then studied by enzyme-linked immunosorbent assay in sera from 40 asymptomatic, hypertensive patients and 105 patients across the spectrum of ventricular dysfunction (32 asymptomatic left ventricular diastolic dysfunction, 26 diastolic HF, and 47 systolic HF patients). Leucine-rich α2-glycoprotein (LRG) was consistently overexpressed in high BNP serum. LRG levels correlate significantly with BNP in hypertensive, asymptomatic left ventricular diastolic dysfunction, diastolic HF, and systolic HF patient groups (P≤0.05). LRG levels were able to identify HF independent of BNP. LRG correlates with coronary sinus serum levels of tumor necrosis factor-α (P=0.009) and interleukin-6 (P=0.021). LRG is expressed in myocardial tissue and correlates with transforming growth factor-βR1 (P<0.001) and α-smooth muscle actin (P=0.025) expression.

CONCLUSIONS: LRG was identified as a serum biomarker that accurately identifies patients with HF. Multivariable modeling confirmed that LRG is a stronger identifier of HF than BNP and this is independent of age, sex, creatinine, ischemia, β-blocker therapy, and BNP.

An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid

Nucleotide-binding oligomerization domain protein 1 (NOD1) belongs to a family that includes multiple members with NOD and leucine-rich repeats in vertebrates and plants. NOD1 has been suggested to have a role in innate immune responses, but the mechanism involved remains unknown. Here we report that NOD1 mediates the recognition of peptidoglycan derived primarily from Gram-negative bacteria. Biochemical and functional analyses using highly purified and synthetic compounds indicate that the core structure recognized by NOD1 is a dipeptide, gamma-D-glutamyl-meso-diaminopimelic acid (iE-DAP). Murine macrophages deficient in NOD1 did not secrete cytokines in response to synthetic iE-DAP and did not prime the lipopolysaccharide response. Thus, NOD1 mediates selective recognition of bacteria through detection of iE-DAP-containing peptidoglycan.

IL-1α and inflammasome-independent IL-1β promote neutrophil infiltration following alum vaccination

Despite its long record of successful use in human vaccines, the mechanisms underlying the immunomodulatory effects of alum are not fully understood. Alum is a potent inducer of interleukin-1 (IL-1) secretion in vitro in dendritic cells and macrophages via Nucleotide-binding domain and leucine-rich repeat-containing (NLR) family, pyrin domain-containing 3 (NLRP3) inflammasome activation. However, the contribution of IL-1 to alum-induced innate and adaptive immune responses is controversial and the role of IL-1α following alum injection has not been addressed. This study shows that IL-1 is dispensable for alum-induced antibody and CD8 T cell responses to ovalbumin. However, IL-1 is essential for neutrophil infiltration into the injection site, while recruitment of inflammatory monocytes and eosinophils is IL-1 independent. Both IL-1α and IL-1β are released at the site of injection and contribute to the neutrophil response. Surprisingly, these effects are NLRP3-inflammasome independent as is the infiltration of other cell populations. However, while NLRP3 and caspase 1 were dispensable, alum-induced IL-1β at the injection site was dependent on the cysteine protease cathepsin S. Overall, these data demonstrate a previously unreported role for cathepsin S in IL-1β secretion, show that inflammasome formation is dispensable for alum-induced innate immunity and reveal that IL-1α and IL-1β are both necessary for alum-induced neutrophil influx in vivo.

Peptide leucine arginine, a potent immunomodulatory peptide isolated and structurally characterized from the skin of the Northern Leopard frog, Rana pipiens

On the basis of histamine release from rat peritoneal mast cells, an octadecapeptide was isolated from the skin extract of the Northern Leopard frog (Rana pipiens), This peptide was purified to homogeneity using reversed-phase high performance liquid chromatography and found to have the following primary structure by Edman degradation and pyridylethylation: LVRGCWTKSYPPKPCFVR, in which Cys(5) and Cys(15) are disulfide bridged. The peptide was named peptide leucine-arginine (pLR), reflecting the N- and C-terminal residues. Molecular modeling predicted that pLR possessed a rigid tertiary loop structure with flexible end regions, pLR was synthesized and elicited rapid, noncytolytic histamine release that had a a-fold greater potency when compared with one of the most active histamine-liberating peptides, namely melittin, pLR was able to permeabilize negatively charged unilamellar lipid vesicles but not neutral vesicles, a finding that was consistent with its nonhemolytic action, pLR inhibited the early development of granulocyte macrophage colonies from bone marrow stem cells but did not induce apoptosis of the end stage granulocytes, i,e. mature neutrophils, pLR therefore displays biological activity with both granulopoietic progenitor cells and mast cells and thus represents a novel bioactive peptide from frog skin.

A peculiar metal-rich star, HD 135485

Local thermodynamic equilibrium (LTE) absolute and differential abundances are presented for a peculiar metal-rich B-type star, HD 135485. These suggest that HD 135485 has a general enrichment of similar to0.5 dex in all the metals observed (C, N, O, Ne, Mg, Al, Si, P, S, Cl, Ar, Sc, Ti, Cr, Mn, Fe and Sr), except for nickel. The helium enhancement and hence hydrogen deficiency can account for less than or equal to 0.2 dex of this enhancement of metals, with the additional enhancement probably being representative of the progenitor gas. However, some of the metals appear to have greater enhancements, which may have occurred during the star's evolution. The significantly larger nitrogen abundance coupled with a modest helium enhancement observed in HD 135485 indicates that carbon- nitrogen (CN) processed material has possibly contaminated the stellar surface. Neon and carbon enhancements may indicate that helium core flashes have also occurred in HD 135485. Some of the iron-group elements (viz. Mn and Ni) appear to have similar abundance patterns to that of silicon Ap stars, but it is uncertain how these abundance patterns formed if they were not present in the progenitor gas. From a kinematical investigation it is unclear whether this star formed in a metal-rich region as implied by its chemical composition. From its position in the Hertzsprung-Russell diagram, HD 135485 would appear to be an evolved star lying close to or on the horizontal branch.

More nitrogen rich B-type stars in the SMC cluster, NGC 330

High resolution spectra of seven early B-type giant/supergiant stars in the SMC cluster NGC330 are analysed to obtain their chemical compositions relative to SMC field and Galactic B-type stars. It is found that all seven stars are nitrogen rich with an abundance approximately 1.3 dex higher than an SMC main- sequence field B-type star, AV304. They also display evidence for deficiencies in carbon, but other metals have abundances typical of the SMC. Given the number of B-type stars with low projected rotational velocities in NGC330 (all our targets have v sin i <50 km s(-1)), we suggest that it is unlikely that the stars in our sample are seen almost pole-on, but rather that they are intrinsically slow rotators. Furthermore, none of our objects displays any evidence of significant Balmer emission excluding the possibility that these are Be stars observed pole-on. Comparing these results with the predictions of stellar evolution models including the effects of rotationally induced mixing, we conclude that while the abundance patterns may indeed be reproduced by these models, serious discrepancies exist. Most importantly, models including the effects of initially large rotational velocities do not reproduce the observed range of effective temperatures of our sample, nor the currently observed rotational velocities. Binary models may be able to produce stars in the observed temperature range but again may be incapable of producing suitable analogues with low rotational velocities. We also discuss the clear need for stellar evolution calculations employing the correct chemical mix of carbon, nitrogen and oxygen for the SMC.

Overexpression of small glutamine-rich TPR-containing protein promotes apoptosis in 7721 cells.

It is known that small glutamine-rich TPR-containing protein (SGT) is the member of TPR motif family. However, the biological functions of SGT remain unclear. In this paper, we report that SGT plays a role in apoptotic signaling. Ectopic expression of SGT enhances DNA fragment and nucleus breakage after the induction of apoptosis. Increasing mRNA level of SGT is also observed in 7721 cells undergoing apoptosis, knockdown the expression of endogenous SGT contributes to the decrease of apoptosis of 7721 cells. Deletion analysis reveals that TPR domain is critical to pro-apoptotic function of SGT. Furthermore, we demonstrated that the PARP cleavage and cytochrome c release are enhanced when SGT is overexpressed in 7721 cells during apoptosis. Collectively, our results indicate that SGT is a new pro-apoptotic factor.

T-cell-rich histiocyte-rich B-cell lymphoma of parotid gland

We describe a malignant lymphoma of the parotid gland arising in a patient with Sjögren's syndrome. Diagnosis was established on needle biopsy which showed a mixed population of lymphoid cells. Immunohistochemistry revealed B-lymphoid cells, T-lymphoid cells and histiocytes. Clonal immunoglobulin heavy chain gene rearrangement was demonstrated using the polymerase chain reaction. Within the confines of the small biopsy, the lesion qualifies for the designation T-cell-rich histiocyte-rich B-cell lymphoma. The value of molecular techniques in the diagnosis of malignant lymphoma on limited tissue samples is highlighted by this case.