The Papillomavirus Episteme (PaVE) is a database of curated papillomavirus genomic sequences, accompanied by web-based sequence analysis tools. This update describes the addition of major new features. The papillomavirus genomes within PaVE have been further annotated, and now includes the major spliced mRNA transcripts. Viral genes and transcripts can be visualized on both linear and circular genome browsers. Evolutionary relationships among PaVE reference protein sequences can be analysed using multiple sequence alignments and phylogenetic trees. To assist in viral discovery, PaVE offers a typing tool; a simplified algorithm to determine whether a newly sequenced virus is novel. PaVE also now contains an image library containing gross clinical and histopathological images of papillomavirus infected lesions. Database URL: https://pave.niaid.nih.gov/.

The goal of the Papillomavirus Episteme (PaVE) is to provide an integrated resource for the analysis of papillomavirus (PV) genome sequences and related information. The PaVE is a freely accessible, web-based tool (http://pave.niaid.nih.gov) created around a relational database, which enables storage, analysis and exchange of sequence information. From a design perspective, the PaVE adopts an Open Source software approach and stresses the integration and reuse of existing tools. Reference PV genome sequences have been extracted from publicly available databases and reannotated using a custom-created tool. To date, the PaVE contains 241 annotated PV genomes, 2245 genes and regions, 2004 protein sequences and 47 protein structures, which users can explore, analyze or download. The PaVE provides scientists with the data and tools needed to accelerate scientific progress for the study and treatment of diseases caused by PVs.

The hematopoietic cell-specific protein Vav1 is a substrate of tyrosine kinases activated following engagement of many receptors, including FcRI. Vav1-deficient mice contain normal numbers of mast cells but respond more weakly than their normal counterparts to a passive systemic anaphylaxis challenge. Vav1-deficient bone marrow-derived mast cells also exhibited reduced degranulation and cytokine production, although tyrosine phosphorylation of FcRI, Syk, and LAT (linker for activation of T cells) was normal. In contrast, tyrosine phosphorylation of phospholipase C␥1 (PLC␥1) and PLC␥2 and calcium mobilization were markedly inhibited. Reconstitution of deficient mast cells with Vav1 restored normal tyrosine phosphorylation of PLC␥1 and PLC␥2 and calcium responses. Thus, Vav1 is essential to FcRI-mediated activation of PLC␥ and calcium mobilization in mast cells. In addition to its known role as an activator of Rac1 GTPases, these findings demonstrate a novel function for Vav1 as a regulator of PLC␥-activated calcium signals.The early events following activation of the high-affinity receptor for immunoglobulin E (IgE) (FcεRI) on mast cells are well studied (32). Like other immunoreceptors, FcεRI contains multiple subunits, the IgE binding ␣ chain, and the ␤ and ␥ chains that function to transduce signals via the paired tyrosine residues of the immunoreceptor tyrosine-based activation motifs (ITAMs) that are found within (45). Aggregation of multiple IgE-occupied FcεRI by polyvalent antigen (Ag) leads to transphosphorylation of the ␤-and ␥-chain ITAMs by the associated Src family protein tyrosine kinase (PTK) Lyn (17,41). This creates a new binding surface for Syk PTK, whose tandem Src homology 2 (SH2) domains facilitate the interaction with the ITAM, resulting in activation of this enzyme (4, 31). Activated Syk then phosphorylates multiple substrates, among which the linker for activation of T cells (LAT) is proximal and essential to FcεRI-activated responses (48). LAT, the SH2 domain-containing leukocyte phosphoprotein of 76 kDa (SLP-76), and phospholipase C␥ (PLC␥) have all been implicated in the regulation of calcium responses in mast cells (40,48,59) and in other cells (12,59,64). These proteins, along with the Rac GTPase-activating Vav1 protein, interact to form a functional macromolecular complex at the plasma membrane that regulates both Rac and Ras signaling (1,14,21,37,51).Vav1 is a cytosolic protein primarily expressed in hematopoietic cells whose structure and function have been extensively examined (6). Its structure includes a calponin homology (CH) domain, a Dbl homology (DH) domain, a pleckstrin homology (PH) domain, a single SH2 domain, and two Src homology 3 (SH3) domains that flank the SH2 domain. Functional studies demonstrated that tyrosine phosphorylation activates Vav's guanine nucleotide exchange factor (GEF) activity for Rho family GTPases (15) with a clear preference for Rac GTPases. Vav1 also promotes intracellular signaling by its C-terminal Grb2-like adapter region, which contains an SH2...