Viral dynamics of primary viremia and antiretroviral therapy in simian immunodeficiency virus infection

Mathematical modeling of viral replication dynamics, based on sequential measurements of levels of virion-associated RNA in plasma during antiretroviral treatment, has led to fundamental new insights into human immunodeficiency virus type 1 pathogenesis. We took advantage of the simian immunodeficiency virus (SIV)-infected macaque model to perform detailed measurements and mathematical modeling during primary infection and during treatment of established infection with the antiretroviral drug (R)-9-(2-phosphonylmethoxypropyl)adenine (PMPA). The calculated clearance half-life for productively infected cells during resolution of the peak viremia of primary infection was on the order of 1 day, with slightly shorter clearance half-lives calculated during PMPA treatment. Viral reproduction rates upon discontinuation of PMPA treatment after 2 weeks were approximately twofold greater than those obtained just prior to initiation of treatment in the same animals, likely reflecting accumulation of susceptible target cells during treatment. The basic reproductive ratio (R0) for the spread of SIV infection in vivo, which represents the number of productively infected cells derived from each productively infected cell at the beginning of infection, was also estimated. This parameter quantifies the extent to which antiviral therapy or vaccination must limit the initial spread of virus to prevent establishment of chronic disseminated infection. The results thus provide an important guide for efforts to develop vaccines against SIV and, by extension, human immunodeficiency virus.     

D-AKAP2, a novel protein kinase A anchoring protein with a putative RGS domain

Subcellular localization directed by specific A kinase anchoring proteins (AKAPs) is a mechanism for compartmentalization of cAMP-dependent protein kinase (PKA). Using a two-hybrid screen, a novel AKAP was isolated. Because it interacts with both the type I and type II regulatory subunits, it was defined as a dual specific AKAP or D-AKAP1. Here we report the cloning and characterization of another novel cDNA isolated from that screen. This new member of the D-AKAP family, D-AKAP2, also binds both types of regulatory subunits. A message of 5 kb pairs was detected for D-AKAP2 in all embryonic stages and in all adult tissues tested. In brain, skeletal muscle, kidney, and testis, a 10-kb mRNA was identified. In testis, several small mRNAs were observed. Therefore, D-AKAP2 represents a novel family of proteins. cDNA cloning from a mouse testis library identified the full length D-AKAP2. It is composed of 372 amino acids which includes the R binding fragment, residues 333-372, at its C-terminus. Based on coprecipitation assays, the R binding domain interacts with the N-terminal dimerization domain of RIalpha and RIIalpha. A putative RGS domain was identified near the N-terminal region of D-AKAP2. The presence of this domain raises the intriguing possibility that D-AKAP2 may interact with a Galpha protein thus providing a link between the signaling machinery at the plasma membrane and the downstream kinase.     

Digital cellular-its roots and its future

Cellular radio started in the early 1980s by using analog technologies. Research in voice coding, modulation, and channel coding resulted in second-generation cellular radio based on digital technologies, which were introduced in the early 1990s. These were all based on advanced time division multiple access technology, resulting in better capacity and lower cost. Today, these digital technologies-based on the Global System for Mobility, digital Advanced Mobile Phone System, and personal digital cellular-have more than 100 million subscribers worldwide. The next step is to introduce wide-band packet services for wireless Internet up to 2 Mb/s. These so-called third-generation systems (Universal Mobile Telecommunications Services, IMT2000) are planned to be introduced in the early 2000s     

Dissolved organic carbon dynamics in the upper rhone: The influence of side-arms?

Dissolved organic carbon (DOC) dynamics were investigated over a two year period in the Upper Rhǒne River to examine the role of side-arms in providing DOC to the main channel in relation to discharge fluctuations, especially floods. Concentrations of DOC are shown to remain low in space and in time (average 1.5 mg ^?1) and to be more related to global hydrological events (precipitation) than to any local flushing for backwaters during floods. The results do not support the general assumption that side-arms are the providers of DOC to the main channel.     

Polymeric prodrugs of mitomycin C designed for tumour tropism and sustained activation

Prodrugs of mitomycin C (MMC) based on soluble poly-[N-(2-hydroxyethyl)-L-glutamine] (pHEG) polymers have been evaluated as tumour-targeted drugs. These materials are designed to exploit the enhanced permeability of tumour vasculature, combining a passive tumour tropism with decreased systemic liberation of free MMC. A tri- or tetrapeptide linkage (e.g. Gly-Phe-Ala-Leu) between pHEG and the aziridine nitrogen of MMC can combine good hydrolytic stability with rapid cleavage by lysosomal enzymes, releasing free MMC. The conjugates showed decreased systemic toxicity and could be administered to mice at a total MMC dose of 15 mg/kg i.v., compared with just 6 mg/kg for free MMC. Conjugates also showed better activity against animal models of established tumours, achieving up to 77% increased life span (ILS) against solid P388 leukaemia, compared with only 23% for free MMC, and up to 121% ILS against solid C26 colorectal carcinoma, compared with no activity for the free drug. Improving the therapeutic index of anticancer drugs by combining tumour tropism with decreased systemic toxicity is a versatile approach that should produce a new generation of improved anticancer agents.     

The effects of cholecystokinin A and B receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in rat

The present study has been divided into two sets. In the first set, the aim of the experiments was to investigate the dose-response effect of selective serotonin re-uptake inhibitor (SSRI) citalopram on rat exploratory behaviour in the elevated plus-maze. In the second set of experiments, the effect of cholecystokinin (CCK) CCKA and CCKB receptor antagonists, devazepide and L 365260, on citalopram-induced decrease of exploratory behaviour in the elevated plus-maze was studied. Citalopram (5 and 10 mg/kg) decreased the number of open and total arm entries, line crossings on open arms, and percentage of time spent exploring in open arm. Dose 15 mg/kg was without any effect on rat exploratory behaviour. Devazepide (0.01 and 1.0 mg/kg) failed to modify any of the citalopram-induced changes observed. L 365260 (1.0 mg/kg) reversed most of the effects of citalopram: the numbers of open and total arm entries, the number of line crossings, and the percentage of time spent exploring in open arms. L 365260 at dose level 0.01 mg/kg was ineffective. These results support the involvement of the CCKB receptor subtype in SSRI-induced anxiogenic-like effects in rodents.     

Impact of crosstalk in an arrayed-waveguide multiplexer onN×N optical interconnection

The impact of crosstalk in an arrayed-waveguide N×N wavelength multiplexer is investigated precisely in relation to its application to wavelength-routing N×N all optical networks. In such systems multiple crosstalk light which has the same wavelength as the signal results in signal-crosstalk beat noise. We confirm that the noise is Gaussian and obtain the relation between crosstalk and power penalty. It is shown that the crosstalk must be less than -38 dB for a 16×16 system to keep the power penalty below 1 dB at a bit error rate of 10^-9     

Complications of chronic otitis media

In summary, recent literature indicates that the complications of chronic otitis media have been decreasing. However, even with the advent of modern and more powerful antimicrobials and aggressive surgical eradication of disease, the morbidity and mortality are still high. Some complications may initially be quite obvious and some complications may be quite subtle. Therefore, the most important tools in making early diagnosis are careful history and physical examination, and a high index of suspicion for impending complications.     

Estimation of linear parametric models of nonGaussian discreterandom fields with application to texture synthesis

A general (possibly asymmetric noncausal and/or nonminimum phase) 2D autoregressive moving average random field model driven by an independent and identically distributed 2D nonGaussian sequence is considered. The model is restricted to be invertible, i.e., system zeros are not allowed to lie on the unit bicircle. Three performance criteria are investigated for parameter estimation of the system parameters given only the output measurements (image pixels). The proposed criteria are functions of the higher order cumulant statistics of an inverse filter output. One of these criteria is novel and the others have been considered in past only for moving average inverses and without any analysis of their consistency. In the paper strong consistency of the proposed methods under the assumption that the system order is known is proved. The convergence of the proposed parameter estimators under overparametrization is also analyzed. Experimental results involving synthesized as well as real life textures are presented to illustrate the performance of two of the considered approaches. Experimental results of synthesis of 128x128 textures visually resembling several real life textures in the Brodatz album (and other sources) are presented.     

An experimental and numerical investigation of ductile crack growth characteristics in surface cracked specimens under combined loading

Fracture mechanics tests have been performed in the upper shelf region of a steel on large surface cracked plate (SCT) specimens and on small compact tension (CT) specimens. Some of the SCT specimens were subjected to combined tension and bending in such a way that the loading was strongly non-proportional. Crack growth characteristics were compared between the specimens in order to assess possible influences of geometry and nonproportional loading. The differences observed could unambiguously be reduced to and correlated with differences in constraint. Constraint parameters were evaluated by detailed three-dimensional finite element computations and quantities for growing cracks were interpreted on the basis of deformation theory considerations, in analogy with the commonly used J _R-philosophy. It was noted that the initiation of ductile crack growth along a three-dimensional crack front appears to be independent of the degree of local constraint. However, the increase in toughness for a growing crack was markedly affected by the degree of local constraint. Some estimates of the constraints effects regarding stability considerations were also made.