Notch receptor cleavage depends on but is not directly executed by presenilins

Notch receptors undergo three distinct proteolytic cleavages during maturation and activation. The third cleavage occurs within the plasma membrane and results in the release and translocation of the intracellular domain into the nucleus to execute Notch signaling. This so-called gamma-secretase cleavage is under the control of presenilins, but it is not known whether presenilins themselves carry out the cleavage or whether they act by means of yet-unidentified gamma-secretase(s). In this article, we show that Notch intracellular cleavage in intact cells completely depends on presenilins. In contrast, partial purification of the Notch cleavage activity reveals an activity, which is present only in protein extracts from presenilin-containing cells, and which does not comigrate with presenilin. This finding provides evidence for the existence of a specific Notch-processing activity, which is physically distinct from presenilins. We conclude from these experiments that presenilins are critically required for Notch intracellular cleavage but are not themselves directly mediating the cleavage.     

Induction of human leukocyte antigen (HLA)-A2-restricted and MAGE-3-gene-derived peptide-specific cytolytic T lymphocytes using cultured dendritic cells from an HLA-A2 esophageal cancer patient.

BACKGROUND AND OBJECTIVES: Using peripheral blood mononuclear cells (PBMCs) from a 10-year survivor with established human leukocyte antigen (HLA)-A2(+) and MAGE-3(+) esophageal cancer cell line (KYSE-170), we examined the induction of HLA-A2-restricted and MAGE-3-gene-derived peptide (FLWGPRALV, amino acids 271-279)-specific cytolytic T lymphocytes (CTLs). METHODS: Autologous dendritic cells (DCs) cultured with granulocyte-macrophage colony stimulating factor and interleukin-4 were used as antigen presenting cells. PBMCs were stimulated by peptide-pulsed DCs in vitro. RESULTS: PBMC cocultured with FLWGPRALV-pulsed DCs could induce the relevant peptide-specific CTLs, which had tumor necrosis factor production and specific cytotoxicity against relevant peptide-pulsed autologous DCs (34%, effector:target ratio = 40:1). Moreover, they showed specific cytotoxicity against the autologous esophageal cancer cell line KYSE-170 (17%, effector:target ratio = 40:1). CONCLUSIONS: These results suggest that FLWGPRALV-pulsed cultured DCs would be a potent candidate for peptide vaccine against HLA-A2(+) and MAGE-3(+) esophageal cancer.     

The contractile mechanism of beraprost sodium,a stable prostacyclin analog,in the isolated canine femoral vein

Summary The vascular contractile mechanism of prostacyclin (PGI₂) was investigated using beraprost sodium (BPS), a stable PGI₂ analog. Ring strips without endothelium isolated from canine femoral veins and arteries were used. BPS induced a dose-dependent contraction without precontraction and after precontraction with norepinephrine (NE) or 60 mM K⁺ in the veins. In contrast, BPS induced a dose-dependent relaxation after precontraction with U46619, a thromboxane A₂ (TXA₂) analog, or prostaglandin F₂ (PGF₂) in the veins. In the arteries, BPS induced contraction at higher concentrations after precontraction with NE. However, BPS relaxed arteries dose-dependently after precontraction with PGF₂. By pretreatment with 13-azaprostanoic acid (13-APA), a TXA₂/endoperoxide receptor antagonist, the dose-response curve of BPS in the veins was shifted to the right. Schild plot analysis resulted in a linear regression with a slope of 0.86 ± 0.13, which was not significantly different from unity, and the pA₂ value for 13-APA against BPS was 7.10 ± 0.06. By pretreatment with BPS, the dose-response curve of U46619 in the veins was shifted to the right. Kaumann plot analysis resulted in a linear regression with a slope of 0.89 ± 0.09, which was not significantly different from unity, and the pA₂ value for BPS against U46619 was 5.68 ± 0.04. These findings indicate that BPS is a partial agonist for the TXA₂/endoperoxide receptors.     

Spacer effect in the template polycondensation of nucleotide analogs with diamines

The template effect of polymers containing the adenine residue, 6 , bound to a polystyrene backbone via a spacer group, on the polycondensation of active esters of thymine, 1 , and theophylline, 2 , with piperazine was studied in pyridine/methylene chloride or DMF. Template polymers accelerated the polycondensation of 1 with diamines by a factor of 5–20, but the polycondensation of 2 with piperazine showed no considerable template effect.     

Yeast ribosomal proteins: XI. Molecular analysis of two genes encoding YL41, an extremely small and basic ribosomal protein,from Saccharomyces cerevisiae

Summary Two genes encoding ribosomal protein YL41 were cloned from Saccharomyces cerevisiae chromosomal DNA. Both genes contain an uniterrupted region of only 75 nucleotides coding for a protein of 3.3 kD. Within the coding regions the nucleotide sequences are virtually identical, whereas in both the 5-and 3-flanking regions the two genes differ significantly from each other. The deduced protein shows an arginine and lysine content of 68 percent, i.e., 17 out of 25 residues, and the basic residues are evenly distributed over the molecule. When compared to the ribosomal protein sequences currently available no counterpart to YL41 could be found in prokaryotes and it seems likely that YL41 is a eukaryotespecific ribosomal protein.     

Mucosal carcinoma within a colonic diverticulum

We report a case of a mucosal carcinoma and adenoma within a diverticulum in the cecum. Radiographic, endoscopic, and pathologic evaluation of the tumor is presented. Surgical resection was undertaken because of the size and shape of the lesion, risk of perforation, and the possibility of malignancy. A recent review of the literature with respect to clinical signs, diagnosis, growth of the carcinoma, and treatment of tumors around or within diverticula is also presented. A carcinoma or adenoma arising within the diverticulum is very rare. Endoscopic resection of the tumor could entail the risk of perforation, because of the lack of muscular coats in the diverticula. Surgical treatment may be the procedure of choice for lesions near or within the diverticula. Received: November 19, 1998 / Accepted: March 26, 1999     

Do panty liners promote vulvovaginal candidiasis or urinary tract infections?: A review of the scientific evidence

Panty liners are used to absorb light menstrual flow, vaginal discharge, or urine leakage, or to maintain a clean, dry feeling. Allegations that panty liners may trap heat and moisture to promote vulvovaginal candidiasis (VVC) or promote colonization by microbes that contribute to urinary tract infections appear to be unfounded. As reviewed herein, measurements of the impact of panty liners on skin temperature and skin surface moisture had no clinically meaningful effect on cell densities of genital microflora. Epidemiological investigations of a potential link to VVC were either negative or were inconclusive because of confounding factors. Although enteric microbes reside on the vulva and perineum, no evidence exists that panty liner use promotes urethral colonization by enteric microbes. Moreover, a series of 13 randomized prospective trials of panty liners or ultra-thin pads demonstrated no clinically significant adverse effects either on the skin or on isolation frequencies or cell densities of representative genital microflora. Post-market surveillance systems suggest a low incidence of complaints. Evidence from vulvar clinic patients reveals no significant contribution of these products to persistent vulvar symptoms. Taken together, the scientific evidence supports the conclusion that panty liners are safe when used as intended and do not promote VVC or urinary tract infections.     

Identification of novel low molecular weight CXCR4 antagonists by structural tuning of cyclic tetrapeptide scaffolds

A highly potent CXCR4 antagonist, compound 2, was previously found by using two orthogonal cyclic pentapeptide libraries involving conformation-based and sequence-based libraries based on the pharmacophore of a 14-mer peptidic antagonist, 1. Herein, cyclic tetrapeptides derived from replacements of the dipeptide unit (Nal-Gly) with a gamma-amino acid and pseudopeptides cyclized by disulfide and olefin bridges were synthesized to find novel scaffold structures different from that of cyclic pentapeptides. These compounds contain a reduced number of peptide bonds compared to compound 2. Furthermore, several analogues with chemical modification of the side chain of Arg(4) in 2 were also prepared. From these, several new leads possessing high to moderate CXCR4-antagonistic activity were characterized.