Blockade of RAGE-amphoterin signalling suppresses tumour growth and metastases

The receptor for advanced glycation end products (RAGE), a multi-ligand member of the immunoglobulin superfamily of cell surface molecules, interacts with distinct molecules implicated in homeostasis, development and inflammation, and certain diseases such as diabetes and Alzheimer's disease. Engagement of RAGE by a ligand triggers activation of key cell signalling pathways, such as p21ras, MAP kinases, NF-kappaB and cdc42/rac, thereby reprogramming cellular properties. RAGE is a central cell surface receptor for amphoterin, a polypeptide linked to outgrowth of cultured cortical neurons derived from developing brain. Indeed, the co-localization of RAGE and amphoterin at the leading edge of advancing neurites indicated their potential contribution to cellular migration, and in pathologies such as tumour invasion. Here we demonstrate that blockade of RAGE-amphoterin decreased growth and metastases of both implanted tumours and tumours developing spontaneously in susceptible mice. Inhibition of the RAGE-amphoterin interaction suppressed activation of p44/p42, p38 and SAP/JNK MAP kinases; molecular effector mechanisms importantly linked to tumour proliferation, invasion and expression of matrix metalloproteinases.     

Evidence against a redshift z > 6 for the galaxy STIS123627+621755

The identification of galaxies at extreme distances provides the most direct information about the earliest phases of galaxy formation. But at redshifts z > 5 even the most luminous galaxies appear faint; the interpretation of low signal-to-noise ratio data is difficult and misidentifications do occur. Here we report optical and near-infrared observations of the source STIS123627+621755, which was previously suggested to be at a redshift of 6.68 (ref. 1). At that redshift, and with the reported spectral energy distribution, the galaxy should be essentially invisible at wavelengths less than 9,300 A, because the intervening intergalactic medium absorbs almost all light energetic enough to ionize neutral hydrogen--that is, with wavelengths less than the redshifted Lyman limit of lambda = (1 + z) x 912A. At near-infrared wavelengths, however, the galaxy should be relatively bright. Here we report a detection of the galaxy at 6,700 A and a non-detection at a wavelength of 1.2 microm, contrary to expectations for z approximately 6.68. The data conservatively require that STIS123627+621755 has a redshift z < 6.     

SCHEDULING IN THE SERVICE INDUSTRIES:AN OVERVIEW

Scheduling plays an important role in many different service industries.In this paper we provide an overview of some of the more important scheduling problems that appear in the various service industries.We focus on the formulations of such problems as well as on the techniques used for solving those problems.We consider five areas of scheduling in service industries,namely(i) project scheduling,(ii) workforce scheduling,(iii) timetabling,reservations,and appointments,(iv)transportation scheduling,and(v) scheduling in entertainment.The first two areas are fairly general and have applications in many different service industries.The third,fourth and fifth areas are more related to some very specific service industries,namely the hospitality and health care industries,the transportation industries(of passengers as well as of cargo),and the entertainment industries.In our conclusion section we discuss the similarities and the differences between the problem formulations and solution techniques used in the various different industries and we also discuss the design of the decision support systems that have been developed for scheduling in the service industries.     

Predominant naturally processed peptides bound to HLA-DR1 are derived from MHC-related molecules and are heterogeneous in size.

Peptides bound to class I molecules are 8-10 amino acids long, and possess a binding motif representative of peptides that bind to a given class I allele. In the only published study of naturally processed peptides bound to class II molecules (mouse I-Ab and I-Eb), these peptides were longer (13-17 amino acids) and had heterogenous carboxy terminals but precise amino-terminal truncations. Here we report the characterization of acid-eluted peptides bound to HLA-DR1 by high-performance liquid chromatography, mass spectrometry and microsequencing analyses. The relative molecular masses of the peptides varied between 1,602 and 2,996 (13-25 residues), the most abundant individual M(r) values being between 1,700 and 1,800, corresponding to an average peptide length of 15 residues. Complete sequence data were obtained for twenty peptides derived from five epitopes, of which all but one were from self proteins. These peptides represented sets nested at both the N- and C-terminal ends. Binding experiments confirmed that all of the isolated peptides had high affinity for the groove of DR1. Alignment of the peptides bound to HLA-DR1 and the sequences of 35 known HLA-DR1-binding peptides revealed a putative motif. Although peptides bound to class II molecules may have some related features (due to the nonpolymorphic HLA-DR alpha-chain), accounting for degenerate binding to different alleles, particular amino acids in the HLA-DR beta-chains presumably define allelic specificity of peptide binding.