An analysis of the major frequency shifts of the optically pumped cesium beam primary frequency standard of the Laboratoire Primaire du Temps et des Frequences (LPTF) is presented, together with a description of the most relevant characteristics of the device. The short-term frequency stability was measured against a hydrogen maser. The square root of the Allan variance /spl sigma//sub y/(/spl tau/) is, at present, 5.8 /spl times/ 10/sup -13/ /spl tau//sup -1/2/, with a flicker level at 3.3 /spl times/ 10//sup -15/. This extremely good frequency stability enables a highly precise analysis of the most important systematic frequency shifts to be performed in a short time. A first accuracy evaluation resulted in an uncertainty (1/spl sigma/) of 1.1 /spl times/ 10/sup -13/.< <ETX xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:xlink="http://www.w3.org/1999/xlink">></ETX>
Fifty years of research (1968-2018) toward the identification of selective antiviral drugs have been primarily focused on antiviral compounds active against DNA viruses (HSV, VZV, CMV, HBV) and retroviruses (HIV). For the treatment of HSV infections the aminoacyl esters of acyclovir were designed, and valacyclovir became the successor of acyclovir in the treatment of HSV and VZV infections. BVDU (brivudin) still stands out as the most potent among the marketed compounds for the treatment of VZV infections (i.e., herpes zoster). In the treatment of HIV infections 10 tenofovir-based drug combinations have been marketed, and tenofovir disoproxil fumarate (TDF) and tenofovir alafenamide (TAF) have also proved effective in the treatment of HBV infections. As a spin-off of our anti-HIV research, a CXCR4 antagonist AMD-3100 was found to be therapeutically useful as a stem cell mobilizer, and has since 10 years been approved for the treatment of some hematological malignancies.
The chemokine receptors CXCR4 and CCR5 are used as co-receptors by the T cell-tropic (X4) and macrophage-tropic (R5) HIV-1 strains, respectively, for entering their host cells. Viral entry can be inhibited by the natural ligands for CXCR4, the CXC chemokine SDF-1 and CCR5, the CC chemokines RANTES, MIP-1alpha and MIP-1beta. Several peptidic compounds, T22 (an 18-mer), T134 (a 14-mer), ALX40-4C (a 9-mer) and CGP 64222 (also a 9-mer), have been identified as CXCR4 antagonists and show anti-HIV activity. Also, the HIV-1 tat protein has been described as a 'natural' CXCR4 antagonist with anti-HIV-1 activity. The most potent and specific CXCR4 antagonists are the bicyclam derivatives, which also potently block X4 HIV replication. AMD3100 has proved to be a highly specific CXCR4 antagonist, which consistently blocks the outgrowth of all X4 HIV and dual-tropic (R5/X4) variants that use CXCR4 for entering the cells (cell lines, CXCR4-transfected cell lines, lymphocytes or monocytes/ macrophages). From the bicyclam analogues, AMD3100 was selected as the clinical drug candidate, which, after initial Phase I (safety) studies, has proceeded to Phase II (efficacy) trials. The first non-peptidic compound that interacts with CCR5, and not with CXCR4, is a quaternary ammonium derivative, called TAK-779, which also has potent but variable anti-HIV activity. We believe that HIV entry/fusion inhibitors will become important new antiviral agents to combat AIDS. However, like the current clinically approved agents, they will need to be used in combinations consisting of antivirals that target other aspects of the HIV replication cycle, such as reverse transcriptase and protease, to obtain optimum therapeutic effects.
The regulation of transcription of the human immunodeficiency virus (HIV) is a complex event that requires the cooperative action of both viral and cellular components. In latently infected resting CD4(+) T cells HIV-1 transcription seems to be repressed by deacetylation events mediated by histone deacetylases (HDACs). Upon reactivation of HIV-1 from latency, HDACs are displaced in response to the recruitment of histone acetyltransferases (HATs) by NF-kappaB or the viral transcriptional activator Tat and result in multiple acetylation events. Following chromatin remodeling of the viral promoter region, transcription is initiated and leads to the formation of the TAR element. The complex of Tat with p-TEFb then binds the loop structures of TAR RNA thereby positioning CDK9 to phosphorylate the cellular RNA polymerase II. The Tat-TAR-dependent phosphorylation of RNA polymerase II plays an important role in transcriptional elongation as well as in other post-transcriptional events. As such, targeting of Tat protein (and/or cellular cofactors) provide an interesting perspective for therapeutic intervention in the HIV replicative cycle and may afford lifetime control of the HIV infection.
Phosphonylmethoxyalkylpurines and -pyrimidines offer great promise for both topical and systemic treatment of various DNA virus and retrovirus infections: HPMPA for the treatment of adeno-, herpes- and poxvirus infections, HPMPC for the treatment of herpesvirus (in particular CMV) infections, and PMEA and PMEDAP for the treatment of retrovirus (i.e. HIV) infections. The efficacy of HPMPA, HPMPC, PMEA and PMEDAP has been demonstrated in various animal model infections, and the further pursuit of their clinical potential seems fully justified. The target for the antiviral action of these compounds appears to be viral DNA synthesis, which they inhibit at a concentration which is far below the concentration required to inhibit cellular DNA synthesis.
This paper has as its focus the integration of Electrical Discharge Machining (EDM) within a Computer Integrated Manufacturing (CIM) environment. Clearly, the induction of EDM into advanced manufacturing system with high levels of computer integration and automated material handling has progressed at a much slower rate than the integration of conventional machining processes such as milling and turning. However, recent developments in communications, controls and CAD/CAM system for EDM have created the potential for bringing EDM into the mainstream of automated machining operations in modern manufacturing systems. Following a brief review of CIM, the paper shows that EDM is a very promising candidate for integration within a CIM environment because of its intrinsic process control and intelligence when compared to many traditional processing techniques. Examples of several rather complete experimental EDM/CIM systems set up within research facilities are described. Conclusions are drawn based upon the experiences gathered to date with these experimental systems.
