4,552 publications from this institution
Transcription is considered to be a crucial step in the replication cycle of HIV-1. Tat regulates an early step of transcription elongation. The positive elongation factor P-TEFb, a heterodimer containing a catalytic subunit (CDK9) and unique regulatory cyclins (CycT1), is required for HIV-1 Tat transcriptional activation. This is a potential target for new HIV-1 transcription inhibitors. Without P-TEFb, transactivation is restrained and only short transcripts are generated. All the P-TEFb inhibitors can suppress the HIV-1 transactivation process by inhibition of CycT1, CDK9 or their interaction. Several low-molecular-weight compounds such as flavopiridol, roscovitine and the human small nuclear RNA 7SK which have been showed to possess potent anti-HIV activity by interfering with P-TEFb functions are reviewed in this article.
Various compounds could be considered to be vaginal microbicides, preventing heterosexual transmission of HIV (i.e. virucidal agents such as nonoxynol 9 and chlorhexidine) and antiviral agents interfering with either virus adsorption/fusion [polyanionic substances such as polysulfates (i.e. PVAS, PAVAS), polysulfonates, polycarboxylates, polyoxometalates and negatively charged albumins], or fusion/uncoating (bicyclams), or reverse transcription [dideoxynucleoside analogues, acyclic nucleoside phosphonates such as PMEA and PMPA, and non-nucleoside reverse transcriptase inhibitors (NNRTIs) such as TIBO, HEPT, and alpha-APA derivatives]. In particular, combination of two or more of these compounds seems to be an attractive approach to interrupt transmission of HIV at different stages of the infectious process.
There are at present exactly 25 compounds that have been formally approved for the treatment of retrovirus (that is HIV) infections: seven nucleoside reverse transcriptase inhibitors (NRTIs), one nucleotide reverse transcriptase inhibitor (NtRTI), four non-nucleoside reverse transcriptase inhibitors (NNRTIs), 10 protease inhibitors (PIs), one coreceptor inhibitor (CRI), one fusion inhibitor (FI) and one integrase inhibitor (INI). Other compounds expected to be approved for the treatment of HIV infections in the near future are the NNRTI rilpivirine, the CRI vicriviroc and the INI elvitegravir. To obtain synergistic activity, enable lower dosage levels, thus minimizing toxic side effects, and particularly to reduce the risk of drug resistance development, common wisdom dictates that the HIV inhibitors should be used in drug combination regimens. Although, given the number of compounds available, the drug combinations that could be concocted are uncountable, only one triple-drug combination has so far been formulated as single pill to be taken orally once daily, namely Atripla containing the NtRTI tenofovir disoproxil fumarate, the NRTI emtricitabine and the NNRTI efavirenz. Here, we document these approved compounds along with other HIV-active compounds and, for the first time, compounds whose principal activity is against hepatitis B virus. The logic of this new division being the enzymatic similarity between the reverse transcriptase of HIV and hepatitis B virus; the strategies for the development of antiviral agents to combat them have much in common.
Additive Manufacturing of Metals via Selective Laser Melting: Process Aspects and Material Developments
The purpose of this study was to investigate if jumping off from a flat take-off support, 0,29 m above the ground, influences specific mechanical and kinesiological variables during the take-off phase. Method 7 male experienced high jumpers (age: 25±6 years; height: 1,88±0,03 m; weight: 75,3±3,3 kg) were filmed doing maximum jumps with normal and increased take-off (height : 0,29 m). Mechanical (movement of C.0.G) and kinesiological (body segment interaction) variables were analysed and compared for both conditions (Wilcoxon). Results and discussion a Mechanical : There is a tendency to a larger maximum flight height of the center of gravity, when jumping with an increased take-off (normal : 1,99 f 0,13 m ; increased: 2,03 ±0,13 m ; NS). This is in contrast with the normal take-off which shows a larger linear impulse, resulting in larger vertical (normal : 3,96 ±0,39 m. sˉ¹; increased: 3,16 ±0,30 m. sˉ¹; p < 0,05) and horizontal (normal : -2,99±0,40 m. sˉ¹; increased: -2,83 ±0,31 m. sˉ¹; NS) changes in velocity during the last contact. When jumping off from the increased take-off, the linear impulse is less because the C.O.G. obtained already a positive vertical velocity (0,64 ±0,10 m.s sˉ¹ ) in the second last step. b. kinesiological : The average radial velocity of the hip of the take-off leg is more negative with a normal take-off (-3,33 f 0,36 m. sˉ¹increased : -3,02 f 0,25 m. sˉ¹; NS) , and reaches also later a positive value, which points to a larger eccentric load of the knee extensor muscles. Normal take-off also shows larger values of the velocity of the knee angle, as well in eccentric (maximal flexion velocity : normal : -621 ±78,8 degrees. sˉ¹; increased : -581±32,3 degrees.sˉ¹;N S) as in concentric status ( normal : 413,4 ±112,7 degrees. sˉ¹ ; increased : 315,l ±71,6 degrees. sˉ¹; p < 0,05). The eccentric-concentric coupling is fluent, while with an increased take-off the knee remains maximally flexed for a rather large period (30 ms). The radial velocity of the swinging leg also contributes to the eccentric-concentric cycle. Conclusion High jumping with an increased take-off tends to lead to a higher jump, probably with a smaller loading of the take-off leg. This can be explained by a more pronounced pre-take-off during the second last foot contact.
This review highlights ten "hot topics" in current antiviral research: (i) new nucleoside derivatives (i.e., PSI-352938) showing high potential as a direct antiviral against hepatitis C virus (HCV); (ii) cyclopropavir, which should be further pursued for treatment of human cytomegalovirus (HCMV) infections; (iii) North-methanocarbathymidine (N-MCT), with a N-locked conformation, showing promising activity against both α- and γ-herpesviruses; (iv) CMX001, an orally bioavailable prodrug of cidofovir with broad-spectrum activity against DNA viruses, including polyoma, adeno, herpes, and pox; (v) favipiravir, which is primarily pursued for the treatment of influenza virus infections, but also inhibits the replication of other RNA viruses, particularly (-)RNA viruses such as arena, bunya, and hanta; (vi) newly emerging antiarenaviral compounds which should be more effective (and less toxic) than the ubiquitously used ribavirin; (vii) antipicornavirus agents in clinical development (pleconaril, BTA-798, and V-073); (viii) natural products receiving increased attention as potential antiviral drugs; (ix) antivirals such as U0126 targeted at specific cellular kinase pathways [i.e., mitogen extracellular kinase (MEK)], showing activity against influenza and other viruses; and (x) two structurally unrelated compounds (i.e., LJ-001 and dUY11) with broad-spectrum activity against virtually all enveloped RNA and DNA viruses.
(E)-5-(2-Bromovinyl)-2'-deoxyuridine (bromovinyldeoxyuridine) was found to suppress the development of herpetic skin lesions and the paralysis and mortality associated therewith in hairless mice inoculated intracutaneously with herpes simplex virus type 1. This protective effect was achieved with bromovinyldeoxyuridine applied topically at 1, 3, or 10% in either dimethylsulfoxide (DMSO), Beeler base, Tween-glycerol-water, 5% Azone (1-dodecylazacycloheptan-2-one) in water, or 5% Azone in DMSO. The optimal vehicle was 5% Azone in DMSO, in which bromovinyldeoxyuridine was effective even at a concentration as low as 0.3%. In its protective activity against cutaneous herpes simplex virus type 1 infection in hairless mice, bromovinyldeoxyuridine was clearly superior to other established antiherpes compounds such as 5-iodo-2'-deoxyuridine, 5-ethyl-2'-deoxyuridine, arabinosyl thymine, and arabinosyl (E)-5-(2-bromovinyl) uracil when formulated at 10% in DMSO or Azone-DMSO. However, no activity was noted with any of these drug formulations against cutaneous herpes simplex virus type 2 infection. In contrast, acycloguanosine (acyclovir) proved quite effective in the topical treatment of cutaneous herpes simplex virus type 2 infection when used at 10% in DMSO or at 5% in propylene glycol.
Abstract Aus den Chinizarinen (I) und dem A Arabinosederivat (II) entstehen die Derivate (III).
The efficient use of commercial CAD/CAM systems for mouldmaking requires the development of application oriented routines and interfaces. Several such specific developments are discussed here. The design of a mould can he speeded up by routines correcting automatically the mould shape in order to compensate for anisotropic shrinkage and by the use of a library of standard mould components, as plates, guides, ejectors, etc. A better link towards mould manufacture has been obtained by the development of a generalized interactive post-processor and a DSC link. A good intepration of CAD/CAM and electro-discharge machinine is achieved in which care is taken of the EDM process planning, the manufacture of the electrodes and the on-line control of the EDM process.
