In pancreatic adenocarcinoma, the presence of CD4+ TILs together with CD8+ TILs serves as a good indicator of the patient's outcome after surgical treatment.

Planarians are considered to be among the most primitive animals which developed the central nervous system (CNS). To understand the origin and evolution of the CNS, we have isolated a neural marker gene from a planarian, Dugesia japonica, and analyzed the structure of the planarian CNS by in situ hybridization. The planarian CNS is located on the ventral side of the body, and composed of a mass of cephalic ganglions in the head region and a pair of ventral nerve cords (VNC). Cephalic ganglions cluster independently from VNC, are more dorsal than VNC, and form an inverted U-shaped brain-like structure with nine branches on each outer side. Two eyes are located on the dorsal side of the 3(rd) branch and visual axons form optic chiasma on the dorsal-inside region of the inverted U-shaped brain. The 6(th)-9(th) branches cluster more closely and form auricles on the surface which may function as the sensory organ of taste. We found that the gross structure of the planarian CNS along the anterior-posterior (A-P) axis is strikingly similar to the distribution pattern of the "primary" neurons of vertebrate embryos which differentiate at the neural plate stage to provide a fundamental nervous system, although the vertebrate CNS is located on the dorsal side. These data suggest that the basic plan for the CNS development along the A-P axis might have been acquired at an early stage of evolution before conversion of the location of the CNS from the ventral to the dorsal side.

Virus-infected fruit bats showed no signs of clinical infection.

Earlier studies have shown that translation elongation factor 1␦ (EF-1␦) is hyperphosphorylated in various mammalian cells infected with representative alpha-, beta-, and gammaherpesviruses and that the modification is mediated by conserved viral protein kinases encoded by herpesviruses, including UL13 of herpes simplex virus type 1 (HSV-1), UL97 of human cytomegalovirus, and BGLF4 of Epstein-Barr virus (EBV). In the present study, we attempted to identify the site in EF-1␦ associated with the hyperphosphorylation by the herpesvirus protein kinases The family Herpesviridae can be divided into three subfamilies (the Alphaherpesvirinae, the Betaherpesvirinae, and the Gammaherpesvirinae), and to date, approximately 130 herpesviruses have been identified from various animal species (41). Despite the wide range of biological properties and pathogenic manifestations of the herpesviruses, their genomes contain a significant number of conserved genes (41). This conservation suggests that the products of these genes play essential roles in the life cycle of herpesviruses. Herpesviruses contain viral genes that are predicted to encode protein kinases (4, 44). Among them, a subset exemplified by UL13 of herpes simplex virus type 1 (HSV-1) is conserved in all of the Herpesviridae (4, 44). Conceivably herpesviruses universally utilize their products both to regulate their own replicative processes and to modify cellular machinery through the phosphorylation of target viral and cellular proteins.HSV-1 UL13, a subject of this study, is a serine/threonine protein kinase that is packaged into the virion (6, 34). Studies with UL13 mutants showed that the viral protein kinase affects the accumulation of an ␣ protein, ICP0, and a subset of ␥ 2 proteins, including UL26, UL26.5, UL38, UL41, and Us11 (37), suggesting that UL13 plays a role in viral gene expression in infected cells. Several lines of evidence listed below indicate that the function of UL13 is closely linked to that of the other viral regulatory proteins ICP22 and Us1.5, both of which are encoded by the ␣22 gene. First, ICP22 and Us1.5 are hypophosphorylated in cells infected with UL13 mutant viruses, suggesting that the UL13 protein kinase phosphorylates these viral regulatory proteins (38). Second, the phenotype of UL13 deletion mutants cannot be differentiated from that of ICP22 and Us1.5 deletion mutant viruses with respect to the accumulation of ICP0 and the subset of ␥ 2 proteins (37). Third, both UL13 and ICP22 and Us1.5 are involved in the HSV-1-induced activation and modification of cellular enzymes, including the protein kinase cdc2 (1) and the large subunit of RNA polymerase II (22). Although this series of observations suggests that UL13 expresses its regulatory function by phosphorylating ICP22 and Us1.5, the direct linkage between phosphorylation

BACKGROUND.Caveolin-1 plays a regulatory role in several signaling pathways.

A gene network involving Notch and Pros underlies the glial regenerative response to injury in the Drosophila central nervous system.

Mutations in the gene encoding the glycosyltransferase polypeptide GalNAc-T3, which is involved in initiation of O-glycosylation, were recently identified as a cause of the rare autosomal recessive metabolic disorder familial tumoral calcinosis (OMIM 211900). Familial tumoral calcinosis is associated with hyperphosphatemia and massive ectopic calcifications. Here, we demonstrate that the secretion of the phosphaturic factor fibroblast growth factor 23 (FGF23) requires O-glycosylation, and that GalNAc-T3 selectively directs O-glycosylation in a subtilisin-like proprotein convertase recognition sequence motif, which blocks processing of FGF23. The study suggests a novel posttranslational regulatory model of FGF23 involving competing O-glycosylation and protease processing to produce intact FGF23.The UDP-GalNAc:polypeptide N-acetylgalactosaminyltransferase (GalNAc-transferase) 2 isoform GalNAc-T3 was recently implicated in familial tumoral calcinosis (FTC) (1, 2). GalNAc-T3 is a member of the large polypeptide GalNAc transferase gene family containing 20 genes of which 15 have been shown to encode functional enzymes. The GalNAc-transferase gene family is the largest mammalian family of glycosyltransferases, which are involved in catalysis of a single glycosidic linkage, GalNAc␣1-O-Ser/Thr, and collectively the GalNAc-transferase isoforms control the initiation of mucin-type O-glycosylation in the Golgi complex (3, 4). Mucin-type O-glycosylation is one of the most abundant forms of glycosylation of proteins, and is found on a large variety of cell membrane and secreted glycopeptides and glycoproteins. O-Glycosylation imparts unique physicochemical features to glycoproteins and O-glycans have been shown to play important functions in almost all known biological processes including intracellular sorting, cell-cell adhesion, and microbial adhesion events (5).Inactivating mutations in GALNT3 were originally discovered in FTC (1, 2, 6, 7), but more recently mutations in the gene encoding the phosphaturic factor FGF23 have also been identified in FTC (8 -10). Thus, FGF23 mutations affecting folding and secretion were identified in FTC patients without mutations in GalNAc-T3. Furthermore, ablation of FGF23 in mice leads to hyperphosphatemia resembling FTC (11). FTC patients with mutations in GalNAc-T3 or FGF23 exhibit hyperphosphatemia and have reduced serum intact FGF23 levels, which may suggest that GalNAc-T3 and FGF23 act in a common pathway. GalNAc-T3 and FGF23 were found to be co-expressed in a number of tissues (2).FGF23 is a key regulator of phosphate homeostasis (12, 13), and is an O-glycosylated glycoprotein of ϳ32 kDa (14). FGF23 is partially processed intracellularly by subtilisin-like proprotein convertases (SPC) at the consensus sequence RXXR2 (RHTR 179 ) between Arg 179 and Ser 180 (14 -16). This processing step appears to be essential in the regulation of phosphate homeostasis, because mutations in the SPC cleavage sequence prevent processing and result in autosomal dominant hypophosphatemic rickets (12). Ma...

We have isolated a novel homeobox gene that is expressed in the vertebrate central nervous system and which shows striking similarity to the Drosophila al gene in the homeodomain (85% identity) and in a 17 amino acid-sequence near the carboxyl-terminus. This gene was designated Arx (aristaless related homeobox gene) in consideration of its structural similarity to the al gene. Arx was highly conserved between mouse and zebrafish. Neuromeric expression in the forebrain and longitudinal expression in the floor plate were observed in mouse and zebrafish. The expression of Arx in the ganglionic eminence and ventral thalamus overlapped regionally with that of Dlx1, but the cell layer where Arx is expressed differed from that of the Dlx1. This gene was also found to be expressed in the dorsal telencephalon (presumptive cerebral cortex) of mouse embryos. The structure and expression pattern of Arx with respect to any possible relationship to al and Dlx1, as well as the function of Arx in the floor plate are discussed.