JC Virus Small t Antigen Binds Phosphatase PP2A and Rb Family Proteins and Is Required for Efficient Viral DNA Replication Activity

BACKGROUND: The human polyomavirus, JC virus (JCV) produces five tumor proteins encoded by transcripts alternatively spliced from one precursor messenger RNA. Significant attention has been given to replication and transforming activities of JCV's large tumor antigen (TAg) and three T' proteins, but little is known about small tumor antigen (tAg) functions. Amino-terminal sequences of tAg overlap with those of the other tumor proteins, but the carboxy half of tAg is unique. These latter sequences are the least conserved among the early coding regions of primate polyomaviruses. METHODOLOGY AND FINDINGS: We investigated the ability of wild type and mutant forms of JCV tAg to interact with cellular proteins involved in regulating cell proliferation and survival. The JCV P99A tAg is mutated at a conserved proline, which in the SV40 tAg is required for efficient interaction with protein phosphatase 2A (PP2A), and the C157A mutant tAg is altered at one of two newly recognized LxCxE motifs. Relative to wild type and C157A tAgs, P99A tAg interacts inefficiently with PP2A in vivo. Unlike SV40 tAg, JCV tAg binds to the Rb family of tumor suppressor proteins. Viral DNAs expressing mutant t proteins replicated less efficiently than did the intact JCV genome. A JCV construct incapable of expressing tAg was replication-incompetent, a defect not complemented in trans using a tAg-expressing vector. CONCLUSIONS: JCV tAg possesses unique properties among the polyomavirus small t proteins. It contributes significantly to viral DNA replication in vivo; a tAg null mutant failed to display detectable DNA replication activity, and a tAg substitution mutant, reduced in PP2A binding, was replication-defective. Our observation that JCV tAg binds Rb proteins, indicates all five JCV tumor proteins have the potential to influence cell cycle progression in infected and transformed cells. It remains unclear how these proteins coordinate their unique and overlapping functions

Expert consensus document:Cholangiocarcinoma: current knowledge and future perspectives consensus statement from the European Network for the Study of Cholangiocarcinoma (ENS-CCA)

Cholangiocarcinoma (CCA) is a heterogeneous group of malignancies with features of biliary tract differentiation. CCA is the second most common primary liver tumour and the incidence is increasing worldwide. CCA has high mortality owing to its aggressiveness, late diagnosis and refractory nature. In May 2015, the "European Network for the Study of Cholangiocarcinoma" (ENS-CCA: www.enscca.org or www.cholangiocarcinoma.eu) was created to promote and boost international research collaboration on the study of CCA at basic, translational and clinical level. In this Consensus Statement, we aim to provide valuable information on classifications, pathological features, risk factors, cells of origin, genetic and epigenetic modifications and current therapies available for this cancer. Moreover, future directions on basic and clinical investigations and plans for the ENS-CCA are highlighted

Port concession fees based on the price-cap regulation: A DEA approach

In Italy, the concessions of port terminals to stevedoring companies are currently governed by the 84/1994 law; notwithstanding Port Authorities have some discretion in charging and defining the fees. As a result, the way concessions fees are charged is not efficient and this will not provide necessary incentives for port operators to boost throughput. This paper suggests an alternative definition for the fee through a price-cap rule, which sets the fee according to the efficiency degree of each port terminal. The efficiency measure is derived from a comparison among a set of competitors, using a data envelopment analysis output-orientated model. In particular, the paper focuses on some of the outstanding results, which are derived from the adoption of the suggested concession's scheme in the main container terminals of the port of Genoa. Maritime Economics & Logistics (2009) 11, 121–135. doi:10.1057/mel.2008.20

The American Association for Thoracic Surgery consensus guidelines on bicuspid aortic valve–related aortopathy: Executive summary

Bicuspid aortic valve disease is a common congenital cardiac disorder, being present in 1% to 2% of the general population. Associated aortopathy is a common finding in patients with bicuspid aortic valve disease, with thoracic aortic dilation noted in approximately 40% of patients in referral centers. Several previous consensus statements and guidelines have addressed the management of bicuspid aortic valve–associated aortopathy, but none focused entirely on this disease process. The current document is an executive summary of “The American Association for Thoracic Surgery Guidelines on Bicuspid Aortic Valve–Related Aortopathy.” All major aspects of bicuspid aortic valve aortopathy, including natural history, phenotypic expression, histology and molecular pathomechanisms, imaging, indications for surgery, surveillance, and follow-up, and recommendations for future research are contained within these guidelines. The current executive summary serves as a condensed version of the guidelines to provide clinicians with a current and comprehensive review of bicuspid aortic valve aortopathy and to guide the daily management of these complex patients

Indirect production function and the output effect of public transit subsidies

Operating subsidy, Capital subsidy, Output effect, Indirect production function, Inefficiency,