9-(trans-2',trans-3'-Dihydroxycyclopent-4'-Enyl)-Adenine and -3-Deazaadenine: Analogs of Neplanocin A Which Retain Potent Antiviral Activity but Exhibit Reduced Cytotoxicity

Two synthetic analogs of neplanocin A, which were shown in a separate study to be inhibitors of S-adenosylhomocysteine hydrolase and devoid of substrate activity with adenosine kinase, were found in this study to inhibit vaccinia virus replication in murine L929 cells but to have reduced cytotoxicity compared with that of the parent compound. These results confirm that S-adenosylhomocysteine hydrolase is the molecular target which mediates the antiviral effects of neplanocin A and that transformation by cellular adenosine kinase mediates its cytotoxic properties.This work was supported by Public Health Service research grant GM-29332 from the National Institutes of Health

Broad-Spectrum Antiviral Activities of Neplanocin A, 3-Deazaneplanocin A, and Their 5'-Nor Derivatives

The neplanocin A analogs, 3-deazaneplanocin A, 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)adenine (DHCA), and 9-(trans-2',trans-3'-dihydroxycyclopent-4'-enyl)-3-deazaadenine (DHCDA), all potent inhibitors of S-adenosylhomocysteine (AdoHcy) hydrolase, were studied for their broad-spectrum antiviral potential. 3-Deazaneplanocin A, DHCA, and DHCDA proved specifically effective against vesicular stomatitis virus, vaccinia virus, parainfluenza virus, reovirus, and rotavirus. Their selectivity was greater than that of neplanocin A, particularly against vesicular stomatitis virus and rotavirus. As could be expected from adenosine analogs that are directly targeted at AdoHcy hydrolase, 3-deazaneplanocin A, DHCA, and DHCDA were fully active in adenosine kinase-deficient cells, implying that their activity did not depend on phosphorylation by adenosine kinase. None of the AdoHcy hydrolase inhibitors showed selective activity against human immunodeficiency virus (type 1). 3-Deazaneplanocin A at a dose of 0.5 mg/kg per day conferred marked protection against a lethal infection of newborn mice with vesicular stomatitis virus.This work was supported by the Belgian Fonds voor Geneeskundig Wetenschappelijk Onderzoek (project no. 3.0040.83) and the Belgian Geconcerteerde Onderzoeksacties (project no. 85/90-79). We thank Anita Van Lierde, Frieda De Meyer, Ria Van Berwaer, Ann Absillis, Etsuko Nitanai, and Willy Zeegers for excellent technical assistance and Christiane Callebaut for fine editorial help

Resource-Restricted Cryptography: Revisiting MPC Bounds in the Proof-of-Work Era

Traditional bounds on synchronous Byzantine agreement (BA) and secure multi-party computation (MPC) establish that in absence of a private correlated-randomness setup, such as a PKI, protocols can tolerate up to $t<n/3$ of the parties being malicious. The introduction of ``Nakamoto style\u27\u27 consensus, based on Proof-of-Work (PoW) blockchains, put forth a somewhat different flavor of BA, showing that even a majority of corrupted parties can be tolerated as long as the majority of the computation resources remain at honest hands. This assumption on honest majority of some resource was also extended to other resources such as stake, space, etc., upon which blockchains achieving Nakamoto-style consensus were built that violated the $t<n/3$ bound in terms of number of party corruptions. The above state of affairs begs the question of whether the seeming mismatch is due to different goals and models, or whether the resource-restricting paradigm can be generically used to circumvent the $n/3$ lower bound. In this work we study this question and formally demonstrate how the above paradigm changes the rules of the game in cryptographic definitions. First, we abstract the core properties that the resource-restricting paradigm offers by means of a functionality wrapper, in the UC framework, which when applied to a standard point-to-point network restricts the ability (of the adversary) to send new messages. We show that such a wrapped network can be implemented using the resource-restricting paradigm---concretely, using PoWs and honest majority of computing power---and that the traditional $t<n/3$ impossibility results fail when the parties have access to such a network. Our construction is in the {\em fresh} Common Reference String (CRS) model---i.e., it assumes a CRS which becomes available to the parties at the same time as to the adversary. We then present constructions for BA and MPC, which given access to such a network tolerate $t<n/2$ corruptions without assuming a private correlated randomness setup. We also show how to remove the freshness assumption from the CRS by leveraging the power of a random oracle. Our MPC protocol achieves the standard notion of MPC security, where parties might have dedicated roles, as is for example the case in Oblivious Transfer protocols. This is in contrast to existing solutions basing MPC on PoWs, which associate roles to pseudonyms but do not link these pseudonyms with the actual parties

Genomic patterns of malignant peripheral nerve sheath tumor (MPNST) evolution correlate with clinical outcome and are detectable in cell-free DNA

Malignant peripheral nerve sheath tumor (MPNST), an aggressive soft-tissue sarcoma, occurs in people with neurofibromatosis type 1 (NF1) and sporadically. Whole-genome and multiregional exome sequencing, transcriptomic, and methylation profiling of 95 tumor samples revealed the order of genomic events in tumor evolution. Following biallelic inactivation of NF1, loss of CDKN2A or TP53 with or without inactivation of polycomb repressive complex 2 (PRC2) leads to extensive somatic copy-number aberrations (SCNA). Distinct pathways of tumor evolution are associated with inactivation of PRC2 genes and H3K27 trimethylation (H3K27me3) status. Tumors with H3K27me3 loss evolve through extensive chromosomal losses followed by whole-genome doubling and chromosome 8 amplification, and show lower levels of immune cell infiltration. Retention of H3K27me3 leads to extensive genomic instability, but an immune cell-rich phenotype. Specific SCNAs detected in both tumor samples and cell-free DNA (cfDNA) act as a surrogate for H3K27me3 loss and immune infiltration, and predict prognosis

Search for New Physics Using Quaero: A General Interface to D0 Event Data

We describe Quaero, a method that i) enables the automatic optimization of searches for physics beyond the standard model, and ii) provides a mechanism for making high energy collider data generally available. We apply Quaero to searches for standard model WW, ZZ, and ttbar production, and to searches for these objects produced through a new heavy resonance. Through this interface, we make three data sets collected by the D0 experiment at sqrt(s)=1.8 TeV publicly available.Comment: 7 pages, submitted to Physical Review Letter

Search for New Physics with Jets and Missing Transverse Momentum in pp collisions at sqrt(s) = 7 TeV

A search for new physics is presented based on an event signature of at least three jets accompanied by large missing transverse momentum, using a data sample corresponding to an integrated luminosity of 36 inverse picobarns collected in proton--proton collisions at sqrt(s)=7 TeV with the CMS detector at the LHC. No excess of events is observed above the expected standard model backgrounds, which are all estimated from the data. Exclusion limits are presented for the constrained minimal supersymmetric extension of the standard model. Cross section limits are also presented using simplified models with new particles decaying to an undetected particle and one or two jets

X-ray emission from the Sombrero galaxy: discrete sources

We present a study of discrete X-ray sources in and around the bulge-dominated, massive Sa galaxy, Sombrero (M104), based on new and archival Chandra observations with a total exposure of ~200 ks. With a detection limit of L_X = 1E37 erg/s and a field of view covering a galactocentric radius of ~30 kpc (11.5 arcminute), 383 sources are detected. Cross-correlation with Spitler et al.'s catalogue of Sombrero globular clusters (GCs) identified from HST/ACS observations reveals 41 X-rays sources in GCs, presumably low-mass X-ray binaries (LMXBs). We quantify the differential luminosity functions (LFs) for both the detected GC and field LMXBs, whose power-low indices (~1.1 for the GC-LF and ~1.6 for field-LF) are consistent with previous studies for elliptical galaxies. With precise sky positions of the GCs without a detected X-ray source, we further quantify, through a fluctuation analysis, the GC LF at fainter luminosities down to 1E35 erg/s. The derived index rules out a faint-end slope flatter than 1.1 at a 2 sigma significance, contrary to recent findings in several elliptical galaxies and the bulge of M31. On the other hand, the 2-6 keV unresolved emission places a tight constraint on the field LF, implying a flattened index of ~1.0 below 1E37 erg/s. We also detect 101 sources in the halo of Sombrero. The presence of these sources cannot be interpreted as galactic LMXBs whose spatial distribution empirically follows the starlight. Their number is also higher than the expected number of cosmic AGNs (52+/-11 [1 sigma]) whose surface density is constrained by deep X-ray surveys. We suggest that either the cosmic X-ray background is unusually high in the direction of Sombrero, or a distinct population of X-ray sources is present in the halo of Sombrero.Comment: 11 figures, 5 tables, ApJ in pres

Performance of the CMS Cathode Strip Chambers with Cosmic Rays

The Cathode Strip Chambers (CSCs) constitute the primary muon tracking device in the CMS endcaps. Their performance has been evaluated using data taken during a cosmic ray run in fall 2008. Measured noise levels are low, with the number of noisy channels well below 1%. Coordinate resolution was measured for all types of chambers, and fall in the range 47 microns to 243 microns. The efficiencies for local charged track triggers, for hit and for segments reconstruction were measured, and are above 99%. The timing resolution per layer is approximately 5 ns

Performance and Operation of the CMS Electromagnetic Calorimeter

The operation and general performance of the CMS electromagnetic calorimeter using cosmic-ray muons are described. These muons were recorded after the closure of the CMS detector in late 2008. The calorimeter is made of lead tungstate crystals and the overall status of the 75848 channels corresponding to the barrel and endcap detectors is reported. The stability of crucial operational parameters, such as high voltage, temperature and electronic noise, is summarised and the performance of the light monitoring system is presented