Synthetic antisense oligodeoxynucleotides as potential drugs against hepatitis C

Antisense oligodeoxynucleotides (ODNS) can be used to specifically inhibit hepatitis C viral gene expression. Due to its high degree of conservation and its important function as internal ribosomal entry site, the 5'-non-coding region of the hepatitis C virus has been the most effective target to inhibit translation so far. Inhibition of luciferase reporter gene expression of up to 96 +/- 2% has been achieved. Modifications of ODNs like phosphorothioate, methylphosphonate or benzylphosphonate modification of terminal or intramolecular internucleotide phosphates lead to altered lipophilicity and binding stability to its RNA target and resistance against serum nucleases. The mode of action of ODNs is mainly dependent on an efficient induction of RNase H activity. The uptake of ODNs occurs via receptor-mediated or absorptive and fluid-phase endocytosis. After release from the endosomes, ODNs may exert their effects by interaction with cytosolic or nuclear structures. Side effects can occur when this interaction affects intra- or extracellular targets essential for biological cell function. If these problems can be solved, antisense technology has the potential for future therapy of human disease.     

Angiotensin-converting enzyme inhibition and angiotensin II subtype-1 receptor blockade during the progression of left ventricular dysfunction: differential effects on myocyte contractile processes

Inhibition of the angiotensin-converting enzyme (ACE) in the setting of chronic left ventricular (LV) dysfunction has been demonstrated to have beneficial effects on survival and symptoms. However, whether ACE inhibition has direct effects on myocyte contractile processes and if these effects are mediated primarily through the AT1 angiotensin-II receptor subtype remains unclear. The present project examined the relationship between changes in LV and myocyte function and beta adrenergic receptor transduction in four groups of six dogs each: (1) Rapid Pace: LV failure induced by chronic rapid pacing (4 weeks; 216 +/- 2 bpm); (2) Rapid Pace/ACEI: concomitant ACE inhibition (ACEI: fosinopril 30 mg/kg b.i.d.) with chronic pacing; (3) Rapid Pace/AT1 Block: concomitant AT1 Ang-II receptor blockade [Irbesartan: SR 47436(BMS-186295) 30 mg/kg b.i.d.] with chronic pacing; and (4) Control: sham controls. With Rapid Pace, the LV end-diastolic volume increased by 62% and the ejection fraction decreased by 53% from control. With Rapid Pace/ACEI, the LV end-diastolic volume was reduced by 24% and the ejection fraction increased by 26% from Rapid Pace only values. Rapid Pace/AT1 Block did not improve LV geometry or function from Rapid Pace values. Myocyte contractile function decreased by 40% with Rapid Pace and increased from this value by 32% with Rapid Pace/ACEI. Rapid Pace/AT1 Block had no effect on myocyte function when compared with Rapid Pace values. With Rapid Pace/ACEI, beta receptor density and cyclic AMP production were normalized and associated with an improvement in myocyte beta adrenergic response compared with Rapid Pace only. Although Rapid Pace/AT1 also normalized beta receptor density, cyclic AMP production was unchanged and myocyte beta adrenergic response was reduced by 15% compared with Rapid Pace only. ACE inhibition with chronic rapid pacing improved LV and myocyte geometry and function, and normalized beta receptor density and cyclic AMP production. However, AT1 Ang-II receptor blockade with chronic rapid pacing failed to provide similar protective effects on LV and myocyte geometry and function. These unique findings suggest that the effects of ACE inhibition on LV geometry and myocyte contractile processes in the setting of developing LV failure are not primarily caused by modulation of AT1 Ang-II receptor activation.     

The influence of oxidation reduction potential and water treatment processes on quartz lamp sleeve fouling in ultraviolet disinfection reactors

Ultraviolet (UV) disinfection systems are incorporated into drinking water production facilities because of their broad-spectrum antimicrobial capabilities, and the minimal disinfection by-product formation that generally accompanies their use. Selection of an optimal location for a UV system within a drinking water treatment facility depends on many factors; a potentially important consideration is the effect of system location on operation and maintenance issues, including the potential for fouling of quartz surfaces. To examine the effect of system location on fouling, experiments were conducted at a groundwater treatment facility, wherein aeration, chlorination, and sand filtration were applied sequentially for treatment. In this facility, access to the water stream was available prior to and following each of the treatment steps. Therefore, it was possible to examine the effects of each of these unit operations on fouling dynamics within a UV system. Results indicated zero-order formation kinetics for the fouling reactions at all locations. Increases in oxidation reduction potential, caused by water treatment steps such as aeration and chlorination, increased the rate of sleeve fouling and the rate of irradiance loss within the reactor. Analysis of metals in the sleeve foulant showed that calcium and iron predominate, and relative comparisons of foulant composition to water chemistry highlighted a high affinity for incorporation into the foulant matrix for both iron and manganese, particularly after oxidizing treatment steps. Fouling behavior was observed to be in qualitative agreement with representations of the degree of saturation, relative to the metal:ligand combinations that are believed to comprise a large fraction of the foulants that accumulate on the surfaces of quartz jackets in UV systems used to treat water.     

Influence of smectite hydration and swelling on atrazine sorption behavior

Smectites, clay minerals commonly found in soils and sediments, vary widely in their ability to adsorb organic chemicals. Recent research has demonstrated the importance of surface charge density and properties of exchangeable cations in controlling the affinity of smectites for organic molecules. In this study, we induced hysteresis in the crystalline swelling of smectites to test the hypothesis that the extent of crystalline swelling (or interlayer hydration status) has a large influence on the ability of smectites to adsorb atrazine from aqueous systems. Air-dried K-saturated Panther Creek (PC) smectite swelled less (d(001) = 1.38 nm) than never-dried K-PC (d(001) = 1.7 nm) when rehydrated in 20 mM KCl. Correspondingly, the air-dried-rehydrated K-PC had an order of magnitude greater affinity for atrazine relative to the never-dried K-PC. Both air-dried-rehydrated and never-dried Ca-PC expanded to approximately 2.0 nm in 10 mM CaCl2 and both samples had similar affinities for atrazine that were slightly lower than that of never-dried K-PC. The importance of interlayer hydration status in controlling sorption affinity was confirmed by molecular modeling, which revealed much greater interaction between interlayer water molecules and atrazine in a three-layer hydrate relative to a one-layer hydrate. The entropy change on moving atrazine from a fully hydrated state in the bulk solution to a partially hydrated state in the smectite interlayers is believed to be a major factor influencing sorption affinity. In an application test, choice of background solution (20 mM KCl versus 10 mM CaCl2) and air-drying treatments significantly affected atrazine sorption affinities for three-smectitic soils; however, the trends were not consistent with those observed for the reference smectite. Further, extending the initial rehydration time from 24 to 240 h (prior to adding atrazine) significantly decreased the soil's sorption affinity for atrazine. We conclude that interlayer hydration status has a large influence on the affinity of smectites for atrazine and that air-drying treatments have the potential to modify the sorption affinity of smectitic soils for organic molecules such as atrazine.     

Using Statistical Regressions to Identify Factors Influencing PM2.5 Concentrations: The Pittsburgh Supersite as a Case Study

Using data from the Pittsburgh Air Quality Study, we find that temperature, relative humidity, their squared terms, and their interactions explain much of the variation in airborne concentrations of PM _2.5 in the city. Factors that do not appreciably influence the concentrations over a full year include wind direction, inverse mixing height, UV radiation, SO ₂ , O ₃ , and season of the year. Comparison with similar studies of PM _2.5 in other cities suggests that the relative importance of different factors can vary greatly. Temperature and relative humidity are important factors in both Pittsburgh and New York City, and synoptic scale meteorology influencing these two sites can explain much of the pattern in PM _2.5 concentrations which peak in the summer. However, PM _2.5 levels in other cities have different seasonal patterns and are affected by a number of other factors, and thus the results presented here cannot be generalized to other locations without additional study.     

Contaminant assimilation within the water column of two newly created prairie wetlands

This research examined the influence of abiotic factors on contaminant assimilation within the water column of two wetlands (RMA3 and RMA4) located on Rocky Mountain Arsenal National Wildlife Area, north of Denver, Colorado, USA. We define contaminant assimilation as the ability of a wetland system to reduce negative impacts of contaminants on aquatic organisms. To examine the influence of abiotic factors (i.e., alkalinity, suspended solids), chronic toxicity tests were performed from February 1992 through November 1993. Ceriodaphnia dubia were exposed to water from the wetlands, which was spiked with Zn. These tests indicated higher assimilative capacity in wetland RMA4 relative to RMA3. Dissolved organic carbon (DOC) was significantly greater in RMA4 than in RMA3, suggesting that it may have influenced differences in bioavailability of Zn in wetland water. Suspended solids were also consistently higher in RMA4 than in RMA3. To test the influence of suspended solids on contaminant assimilation, C. dubia were exposed to filtered and unfiltered Zn-spiked water from RMA4. The greater toxicity of Zn to C. dubia in filtered water indicated that suspended solids were important in ameliorating impacts of Zn in RMA4. Results from this study suggest that from the suite of variables assessed, DOC and suspended solids were the most important physiochemical influences on Zn toxicity within the water column of these two wetlands. Differences in habitat characteristics of RMA3 and RMA4 demonstrated the importance of site-selection toward functional design of wetlands.     

Probability Distribution Functions for Construction Simulation

The need for reliable simulation systems has been discussed and recognized by many researchers. At the same time researchers have recognized that the quality of a simulation model's results are strictly related to the quality of the input probability distribution functions. The data used in this research were acquired from the Atkinson-Washington-Zachry joint venture on the Eastside Reservoir Project in California. The data were analyzed using BestFit software to obtain the parameters of the theoretical distribution functions that best described the field data set. The research validated previous warnings about the influence of the class interval decision on the selection of a distribution function when the chi-square fitting test is utilized. A second issue of importance that was encountered was the reliability of goodness-of-fit tests when dealing with large data sets.     

10大最具创意的建筑师

已经很少有建筑师像Will Alsop一样，如此致力于这种不同寻常的设计美学。更少有人能如此成功地实现自己的设计。马上建设完成的“芯片”大厦的设计灵感就是来自于堆积的薯条；而这个安大略艺术设计学院的扩建部分在最近一段时期的建筑中是最奇怪、最令人兴奋的。Will Alsop（1947年11月12日生）是一位出生在伦敦的英国建筑师。他对大部分出现在英国的一些独特的和有争议的现代建筑负有责任。AlsopA9建筑经常因其充满活力的色彩运用和不一般的形式而显得非同寻常。