Counteracting HIV-1 protease drug resistance: structural analysis of mutant proteases complexed with XV638 and SD146, cyclic urea amides with broad specificities

The long-term therapeutic benefit of HIV antiretroviral therapy is still threatened by drug-resistant variants. Mutations in the S1 subsite of the protease are the primary cause for the loss of sensitivity toward many HIV protease inhibitors, including our first-generation cyclic urea-based inhibitors DMP323 and DMP450. We now report the structures of the three active-site mutant proteases V82F, I84V, and V82F/I84V in complex with XV638 and SD146, two P2 analogues of DMP323 that are 8-fold more potent against the wild type and are able to inhibit a broad panel of drug-resistant variants [Jadhav, P. K., et al. (1997) J. Med. Chem. 40, 181-191]. The increased efficacy of XV638 and SD146 is due primarily to an increase in P2-S2 interactions: 30-40% more van der Waals contacts and two to four additional hydrogen bonds. Furthermore, because these new interactions do not perturb other subsites in the protease, it appears that the large complementary surface areas of their P2 substituents compensate for the loss of P1-S1 interactions and reduce the probability of selecting for drug-resistant variants.     

Peripherally inserted central catheters in an acute-care hospital

BACKGROUND: Peripherally inserted central catheterization is a relatively new approach for intravenous therapy in acute-care hospitals. Few studies are available on peripherally inserted central catheters (PICCs) used in adult patients in an acute-care setting. We examine the natural history and outcome of PICC use in our hospital. METHODS: A retrospective review was undertaken of all hospitalized patients who had PICCs inserted in an acute-care, metropolitan teaching hospital for any reason from July 1991 through July 1992. Patients who had PICCs inserted, used, and then removed in the same hospitalization were evaluated. RESULTS: A total of 135 PICCs were inserted in 114 patients. Six PICCs (4.4%) were inserted in intensive care unit settings and 129 (95.6%) in general medical or surgical service. The mean duration catheters were in place before removal was 14.1 days. Sixty-three catheters (46.7%) were removed following completion of therapy. The rate of PICC-related infection was 2.2% (three catheters). The occlusion rate was higher for 20-gauge catheters (18.4%) than for 18-gauge catheters (8.2%) (P = .08). When the rate of complications was compared as a function of catheter use (total parenteral nutrition vs any other use), there was no statistically significant difference (P = .12). Overall complications related to catheter insertion and removal were uncommon. CONCLUSIONS: Based on our study, we conclude that the PICC provides a reasonable and safe alternative to other centrally placed venous devices. In addition, the convenience of maintaining a PICC compared with peripheral intravenous access makes this an attractive method for in-hospital use.     

MQAM和MPSK在Nakagami衰落信道中的BER性能

基于AWGN信道中MQAM和MPSK的BER性能的近似准确分析结果，本文导出并分析了MQAM和MPSK在Nakagami-m衰落信道中采用或不采用MRC分集时的BER性能。分析结果表明，在AWGN信道、瑞利衰落信道甚至莱斯衰落信道下，现有采用或不采用MRC分集的系统性能分析结果均可以作为本文分析结果的特例。     

Learning to Understand Information on the Internet: An Example-Based Approach

The explosive growth of the Web has made intelligent softwareassistants increasingly necessary for ordinary computer users. Bothtraditional approaches—search engines, hierarchical indices—andintelligent software agents require significant amounts of humaneffort to keep up with the Web. As an alternative, we investigate theproblem of automatically learning to interact with informationsources on the Internet. We report on ShopBotand ILA , two implemented agents that learn touse such resources. ShopBot learns how to extract information from onlinevendors using only minimal knowledge about product domains. Giventhe home pages of several online stores, ShopBotautonomously learns how to shop at those vendors. After its learningis complete, ShopBot is able to speedily visitover a dozen software stores and CD vendors, extract productinformation, and summarize the results for the user. ILAlearns to translate information from Internetsources into its own internal concepts. ILAbuilds a model of an information source that specifies the translation between the source's output and ILA 's model of the world. ILA iscapable of leveraging a small amount of knowledge about a domain tolearn models of many information sources. We show that ILA 's learning is fast and accurate, requiring only a smallnumber of queries per information source.     

Transdermal fentanyl for severe cancer-related pain

This paper reports on the analysis of 332 otosclerosis revision operations. The results have been evaluated with reference to the type of the procedure at primary surgery, the alleged cause of failure and the applied technical solution. The need for revision surgery was found higher after primary total stapedectomy (3.4 per cent) than after partial stapedectomy (2.2 per cent) or stapedectomy (two per cent). The reason for revision varied according to the originally applied technique eg a migrated piston, a too short piston and a lateralized graft are almost exclusively found after total stapedectomies. The median hearing gain after revision of stapedectomy and partial stapedectomy was higher (20 dB and 18 dB respectively) than that after revision surgery for total stapedectomy (12 dB), but significantly lower than hearing gain after primary surgery (32 dB). Revisions yielded better results in the case of primary interventions with the use of a piston or pistonwire than in the case of primary interventions with a wire-type prosthesis. The risk for sensorineural loss (one per cent) was not higher than in primary surgery.     

Pole assignment with optimal spectral conditioning

This paper presents a novel method for pole assignment with robustness measured in terms of the spectral condition number of the closed-loop eigenvector matrix. It is established that the spectral condition number can be minimized asymptotically via a sequence of unconstrained minimizations on some auxiliary objective functions. Moreover, the sequence of minimizers converges to a minimizer of the spectral condition number. A numerical algorithm with analytical formulas of the gradient of the auxiliary objective functions is provided. The efficiency and effectiveness of the approach is demonstrated via an example.     

Monolithic integration of GaAs photoconductors with a field-effect transistor

A one-stage monolithic integration of a tandem pair of GaAs photoconductors (PCs) with a field-effect transistor (FET) is reported. The PC-FET exhibits a bandwidth in excess of 1 GHz and a gain of 6 dB at midband. A very low noise figure of ~3 dB in the FET is also achieved.     

Transverse vibration of symmetrically laminated rectangular composite plates

A general numerical method for estimation of the vibrational response of symmetrically laminated rectangular composite plates is presented. This is based on the Rayleigh-Ritz method using the admissible 2-D orthogonal polynomials to derive the governing eigenvalue equation. The natural frequencies and mode shapes for the laminated plates are obtained by solving this governing eigenvalue equation. Several test problems are solved to demonstrate the accuracy and flexibility of the proposed method. The present results, where possible, are verified with those available values from the literature. The effects of the material, number of layers and fibre orientation upon the frequencies and mode shapes are discussed. This study may provide valuable information for researchers and engineers in design applications.