Detection of hepatitis C virus in the nasal secretions of an intranasal drug-user

BACKGROUND: One controversial source of infection for hepatitis C virus (HCV) involves the sharing of contaminated implements, such as straws or spoons, used to nasally inhale cocaine and other powdered drugs. An essential precondition for this mode of transmission is the presence of HCV in the nasal secretions of intranasal drug users. METHODS: Blood and nasal secretion samples were collected from five plasma-positive chronic intranasal drug users and tested for HCV RNA using RT-PCR. RESULTS: HCV was detected in all five blood samples and in the nasal secretions of the subject with the highest serum viral load. CONCLUSIONS: This study is the first to demonstrate the presence of HCV in nasal secretions. This finding has implications for potential transmission of HCV through contact with contaminated nasal secretions

Trinucleotide cassettes increase diversity of T7 phage-displayed peptide library

<p>Abstract</p> <p>Background</p> <p>Amino acid sequence diversity is introduced into a phage-displayed peptide library by randomizing library oligonucleotide DNA. We recently evaluated the diversity of peptide libraries displayed on T7 lytic phage and M13 filamentous phage and showed that T7 phage can display a more diverse amino acid sequence repertoire due to differing processes of viral morphogenesis.</p> <p>Methods</p> <p>In this study, we evaluated and compared the diversity of a 12-mer T7 phage-displayed peptide library randomized using codon-corrected trinucleotide cassettes with a T7 and an M13 12-mer phage-displayed peptide library constructed using the degenerate codon randomization method.</p> <p>Results</p> <p>We herein demonstrate that the combination of trinucleotide cassette amino acid codon randomization and T7 phage display construction methods resulted in a significant enhancement to the functional diversity of a 12-mer peptide library. This novel library exhibited superior amino acid uniformity and order-of-magnitude increases in amino acid sequence diversity as compared to degenerate codon randomized peptide libraries. Comparative analyses of the biophysical characteristics of the 12-mer peptide libraries revealed the trinucleotide cassette-randomized library to be a unique resource.</p> <p>Conclusion</p> <p>The combination of T7 phage display and trinucleotide cassette randomization resulted in a novel resource for the potential isolation of binding peptides for new and previously studied molecular targets.</p

Price Discovery and the Accuracy of Consolidated Data Feeds in the U.S. Equity Markets

Both the scientific community and the popular press have paid much attention to the speed of the Securities Information Processor, the data feed consolidating all trades and quotes across the US stock market. Rather than the speed of the Securities Information Processor, or SIP, we focus here on its accuracy. Relying on Trade and Quote data, we provide various measures of SIP latency relative to high-speed data feeds between exchanges, known as direct feeds. We use first differences to highlight not only the divergence between the direct feeds and the SIP, but also the fundamental inaccuracy of the SIP. We find that as many as 60 percent or more of trades are reported out of sequence for stocks with high trade volume, therefore skewing simple measures such as returns. While not yet definitive, this analysis supports our preliminary conclusion that the underlying infrastructure of the SIP is currently unable to keep pace with the trading activity in today's stock market.Comment: 18 pages, 20 figures, 2 table

Erioflorin stabilizes the tumor suppressor Pdcd4 by inhibiting its interaction with the E3-ligase β-TrCP1

Loss of the tumor suppressor Pdcd4 was reported for various tumor entities and proposed as a prognostic marker in tumorigenesis. We previously characterized decreased Pdcd4 protein stability in response to mitogenic stimuli, which resulted from p70S6K1-dependent protein phosphorylation, β-TrCP1-mediated ubiquitination, and proteasomal destruction. Following high-throughput screening of natural product extract libraries using a luciferase-based reporter assay to monitor phosphorylation-dependent proteasomal degradation of the tumor suppressor Pdcd4, we succeeded in showing that a crude extract from Eriophyllum lanatum stabilized Pdcd4 from TPA-induced degradation. Erioflorin was identified as the active component and inhibited not only degradation of the Pdcd4-luciferase-based reporter but also of endogenous Pdcd4 at low micromolar concentrations. Mechanistically, erioflorin interfered with the interaction between the E3-ubiquitin ligase β-TrCP1 and Pdcd4 in cell culture and in in vitro binding assays, consequently decreasing ubiquitination and degradation of Pdcd4. Interestingly, while erioflorin stabilized additional β-TrCP-targets (such as IκBα and β-catenin), it did not prevent the degradation of targets of other E3-ubiquitin ligases such as p21 (a Skp2-target) and HIF-1α (a pVHL-target), implying selectivity for β-TrCP. Moreover, erioflorin inhibited the tumor-associated activity of known Pdcd4- and IκBα-regulated αtranscription factors, that is, AP-1 and NF-κB, altered cell cycle progression and suppressed proliferation of various cancer cell lines. Our studies succeeded in identifying erioflorin as a novel Pdcd4 stabilizer that inhibits the interaction of Pdcd4 with the E3-ubiquitin ligase β-TrCP1. Inhibition of E3-ligase/target-protein interactions may offer the possibility to target degradation of specific proteins only as compared to general proteasome inhibition

Desferrioxamine biosynthesis : diverse hydroxamate assembly by substrate-tolerant acyl transferase DesC

Hydroxamate groups play key roles in the biological function of diverse natural products. Important examples include trichostatin A, which inhibits histone deacetylases via coordination of the active site zinc(II) ion with a hydroxamate group, and the desferrioxamines, which use three hydroxamate groups to chelate ferric iron. Desferrioxamine biosynthesis in Streptomyces species involves the DesD-catalysed condensation of various N-acylated derivatives of N-hydroxycadaverine with two molecules of N-succinyl-N-hydroxycadaverine to form a range of linear and macrocyclic tris-hydroxamates. However, the mechanism for assembly of the various N-acyl-N-hydroxycadaverine substrates of DesD from N-hydroxycadaverine has until now been unclear. Here we show that the desC gene of Streptomyces coelicolor encodes the acyl transferase responsible for this process. DesC catalyses the N-acylation of N-hydroxycadaverine with acetyl, succinyl and myristoyl-CoA, accounting for the diverse array of desferrioxamines produced by S. coelicolor. The X-ray crystal structure of DesE, the ferrioxamine lipoprotein receptor, in complex with ferrioxamine B (which is derived from two units of N-succinyl-N-hydroxycadaverine and one of N-acetyl-N-hydroxycadaverine) was also determined. This shows that the acetyl group of ferrioxamine B is solvent exposed, suggesting that the corresponding acyl group in longer chain congeners can protrude from the binding pocket, providing insights into their likely functio

The characteristics of cognitive neuroscience tests in a schizophrenia cognition clinical trial: Psychometric properties and correlations with standard measures.

In comparison to batteries of standard neuropsychological tests, cognitive neuroscience tests may offer a more specific assessment of discrete neurobiological processes that may be aberrant in schizophrenia. However, more information regarding psychometric properties and correlations with standard neuropsychological tests and functional measures is warranted to establish their validity as treatment outcome measures. The N-back and AX-Continuous Performance Task (AX-CPT) are two promising cognitive neuroscience tests designed to measure specific components of working memory and contextual processing respectively. In the current study, we report the psychometric properties of multiple outcome measures from these two tests as well as their correlations with standard neuropsychological measures and functional capacity measures. The results suggest that while the AX-CPT and N-back display favorable psychometric properties, they do not exhibit greater sensitivity or specificity with functional measures than standard neurocognitive tests

Altered Tendon Characteristics and Mechanical Properties Associated with Insertional Achilles Tendinopathy

Study Design: Case-control laboratory study. Objectives: To compare tendon characteristics (shape, composition) and mechanical properties (strain, stiffness) on the involved side of participants with insertional Achilles tendinopathy (IAT) to the uninvolved side and to controls, and to examine if severity of tendon pathology is associated with severity of symptoms during function. Background: Despite the severity and chronicity of IAT, the quality of theoretical evidence available to guide the development of exercise interventions is low. While tendon pathology of midportion Achilles tendinopathy has been described, there are few studies specific to IAT. Methods: Twenty individuals with unilateral IAT and 20 age- and sex-matched controls volunteered to participate. Ultrasound imaging was used to quantify changes in tendon shape (diameter) and composition (echogenicity). A combination of ultrasound and dynamometry was used to measure tendon mechanical properties (strain and stiffness) during passive ankle rotation toward dorsiflexion. Generalized estimating equations were used to examine the association between IAT, alterations in tendon properties, and participant demographics. Pearson correlation was used to examine the association between severity of tendon pathology and severity of symptoms (Victorian Institute of Sport Assessment-Achilles). Results: The side with IAT had a larger tendon diameter (P Conclusion: Ultrasound imaging combined with dynamometry can discriminate alterations in tendon shape, composition, and mechanics in participants with IAT. Future clinical trials for IAT may consider strategies to alter tendon characteristics and restore tendon mechanic

Oligosaccharide and Glycoprotein Microarrays as Tools in HIV Glycobiology Glycan-Dependent gp120/Protein Interactions

AbstractDefining HIV envelope glycoprotein interactions with host factors or binding partners advances our understanding of the infectious process and provides a basis for the design of vaccines and agents that interfere with HIV entry. Here we employ carbohydrate and glycoprotein microarrays to analyze glycan-dependent gp120-protein interactions. In concert with new linking chemistries and synthetic methods, the carbohydrate arrays combine the advantages of microarray technology with the flexibility and precision afforded by organic synthesis. With these microarrays, we individually and competitively determined the binding profiles of five gp120 binding proteins, established the carbohydrate structural requirements for these interactions, and identified a potential strategy for HIV vaccine development

Dictyostelium Myosin Bipolar Thick Filament Formation: Importance of Charge and Specific Domains of the Myosin Rod

Myosin-II thick filament formation in Dictyostelium is an excellent system for investigating the phenomenon of self-assembly, as the myosin molecule itself contains all the information required to form a structure of defined size. Phosphorylation of only three threonine residues can dramatically change the assembly state of myosin-II. We show here that the C-terminal 68 kDa of the myosin-II tail (termed AD-Cterm) assembles in a regulated manner similar to full-length myosin-II and forms bipolar thick filament (BTF) structures when a green fluorescent protein (GFP) “head” is added to the N terminus. The localization of this GFP-AD-Cterm to the cleavage furrow of dividing Dictyostelium cells depends on assembly state, similar to full-length myosin-II. This tail fragment therefore represents a good model system for the regulated formation and localization of BTFs. By reducing regulated BTF assembly to a more manageable model system, we were able to explore determinants of myosin-II self-assembly. Our data support a model in which a globular head limits the size of a BTF, and the large-scale charge character of the AD-Cterm region is important for BTF formation. Truncation analysis of AD-Cterm tail fragments shows that assembly is delicately balanced, resulting in assembled myosin-II molecules that are poised to disassemble due to the phosphorylation of only three threonines

An Assessment Of The Forces Acting Upon A Centrifugal Impeller Using Full Load, Full Pressure Hydrocarbon Testing.

LecturePg. 111-122Although turbocompressors have been designed, built, and used in increasingly stringent conditions for more than 80 years, the turbomachinery industry, like all comparable industries, can only design and manufacture its products within the realm of existing knowledge and foreseeable operating, engineering, and scientific parameters. As end users of turbocompressors continue to implement ever more complex and demanding assortments of processes and process variables into their operations (i.e., equipment efficiencies, higher pressures, and the like), previously unseen combinations of factors can create new and unpredictable forces and effects on equipment. These unpredictable forces may, at different times, cause destructive results in the end user's facility, such as in piping, valves, gauges, tanks, etc. It is possible for these forces, which may only exist under the unique circumstances present at the end user's site, occasionally to manifest themselves in the centrifugal compressor rotor. When this occurs, the rotors may exhibit such phenomena as rotordynamic excitation, less than anticipated aerothermal performance, or even a physical failure of a rotor or other component. When this unfortunate circumstance occurs, turbocompressor OEMs dedicated to both customer satisfaction and continued expansion of knowledge and technical responsiveness, will investigate (typically in cooperation with the end user) to determine, if possible, the full range of dynamics that may be occurring during process operation at the end user's site, so that the turbomachines can, if possible, be made to withstand the unforeseen forces. These efforts typically involve some combination of analytical studies and research testing; analytical work to provide a sound computational model, and testing to provide the data necessary to calibrate or bound the models. The test program and results described herein represent an OEMs and end user's efforts to identify the cause of repeated impeller failures in an offshore gas reinjection compressor. A machine identical to the field units was fully instrumented with aerodynamic and mechanical instrumentation (including radial and axial vibration probes, dynamic and static straingauges, dynamic pressure transducers, and other interstage pressure and temperature instrumentation). The compressor was then tested at full load and full pressure on hydrocarbon gas at the OEMs facility. Descriptions of the instrumentation and test procedure are provided. Concurrently, analytical efforts were undertaken to help understand the aerodynamic forces that may be contributing to the failures. Results from both the testing and the computational studies are presented along with the conclusions derived from both efforts