Bivalent IAP antagonists, but not monovalent IAP antagonists, inhibit TNF-mediated NF-κB signaling by degrading TRAF2-associated cIAP1 in cancer cells.

The inhibitor of apoptosis (IAP) proteins have pivotal roles in cell proliferation and differentiation, and antagonizing IAPs in certain cancer cell lines results in induction of cell death. A variety of IAP antagonist compounds targeting the baculovirus IAP protein repeat 3 (BIR3) domain of cIAP1have advanced into clinical trials. Here we sought to compare and contrast the biochemical activities of selected monovalent and bivalent IAP antagonists with the intent of identifying functional differences between these two classes of IAP antagonist drug candidates. The anti-cellular IAP1 (cIAP1) and pro-apoptotic activities of monovalent IAP antagonists were increased by using a single covalent bond to combine the monovalent moieties at the P4 position. In addition, regardless of drug concentration, treatment with monovalent compounds resulted in consistently higher levels of residual cIAP1 compared with that seen following bivalent compound treatment. We found that the remaining residual cIAP1 following monovalent compound treatment was predominantly tumor necrosis factor (TNF) receptor-associated factor 2 (TRAF2)-associated cIAP1. As a consequence, bivalent compounds were more effective at inhibiting TNF-induced activation of p65/NF-κB compared with monovalent compounds. Moreover, extension of the linker chain at the P4 position of bivalent compounds resulted in a decreased ability to degrade TRAF2-associated cIAP1 in a manner similar to monovalent compounds. This result implied that specific bivalent IAP antagonists but not monovalent compounds were capable of inducing formation of a cIAP1 E3 ubiquitin ligase complex with the capacity to effectively degrade TRAF2-associated cIAP1. These results further suggested that only certain bivalent IAP antagonists are preferred for the targeting of TNF-dependent signaling for the treatment of cancer or infectious diseases.

Control and coupling of spiral waves in excitable media.

We report the complex dynamics of spiral waves observed in the ferroin-catalyzed BZ reaction. The reaction is run in an open unstirred reactor (CFUR) with the catalyst immobilized on a polysulfone membrane. The catalyst-loaded membrane is placed between two well stirred compartments which are fed with solutions of sulfuric acid/malonic acid/bromide and sulfuric acid/bromate, respectively. An electrical field perpendicular to the membrane can be applied via Pt-ring electrodes or, alternatively, via transparent electrodes made of ITO-coated glass. In the field-free case relatively simple target and spiral patterns are observed in the membrane. If an alternating electrical field is applied the spiral core drifts through the membrane. The actual trajectory of the spiral tip depends on the amplitude and frequency of the applied electrical field. If the perturbation parameters are chosen properly the wave fronts break up and new spiral cores emerge under the influence of the alternating field. Complex spatio-temporal patterns may be induced which are reminiscent of "spiral-chaos". After switching off the perturbation the system returns to its previous, "simple" behaviour. Our experimental observations are confirmed by model calculations based on the Barkley model of spiral waves. The technique of using modulated excitability to control the dynamics of spiral waves is further extended to the coupling of two spirals in two CFURs. We present numerical simulations based on two identical excitable reaction-diffusion (RD) systems which are mutually coupled. The coupling is based on the observation of an arbitrarily chosen point inside each of the RD systems: If a chemical wave passes the point of optical observation in system 1 an electric field is applied to system 2 and vice versa. Thus, a local observation made in one system is transformed in a global perturbation of the second CFUR. We report the observation of CFUR states where the two spiral waves are spatially and temporally coupled to each other.

Complex behaviour of spiral waves induced by an alternating electric field.

An efficient control of chemical waves is desirable in various fields of science and engineering. We present a novel method to control the motion of the spiral tip using an electric field perpendicular to the plane of wave propagation. An alternating field may lead to complex spatio-temporal patterns. Shown in the picture is an example of the destabilising effect of an alternating electric field, in which the wavefront displays fluctuating wrinkles.

Mechanism of action of a pestivirus antiviral compound.

We report here the discovery of a small molecule inhibitor of pestivirus replication. The compound, designated VP32947, inhibits the replication of bovine viral diarrhea virus (BVDV) in cell culture at a 50% inhibitory concentration of approximately 20 nM. VP32947 inhibits both cytopathic and noncytopathic pestiviruses, including isolates of BVDV-1, BVDV-2, border disease virus, and classical swine fever virus. However, the compound shows no activity against viruses from unrelated virus groups. Time of drug addition studies indicated that VP32947 acts after virus adsorption and penetration and before virus assembly and release. Analysis of viral macromolecular synthesis showed VP32947 had no effect on viral protein synthesis or polyprotein processing but did inhibit viral RNA synthesis. To identify the molecular target of VP32947, we isolated drug-resistant (DR) variants of BVDV-1 in cell culture. Sequence analysis of the complete genomic RNA of two DR variants revealed a single common amino acid change located within the coding region of the NS5B protein, the viral RNA-dependent RNA polymerase. When this single amino acid change was introduced into an infectious clone of drug-sensitive wild-type (WT) BVDV-1, replication of the resulting virus was resistant to VP32947. The RNA-dependent RNA polymerase activity of the NS5B proteins derived from WT and DR viruses expressed and purified from recombinant baculovirus-infected insect cells confirmed the drug sensitivity of the WT enzyme and the drug resistance of the DR enzyme. This work formally validates NS5B as a target for antiviral drug discovery and development. The utility of VP32947 and similar compounds for the control of pestivirus diseases, and for hepatitis C virus drug discovery efforts, is discussed.

Tax reform for low-wage workers.

As a result of the recent implementation of work-oriented antipoverty programs, more welfare recipients can be expected to be working in low-wage jobs. With these jobs there is little hope that these workers' incomes will rise above the poverty level. One way to help support these low-wage workers is through tax reform. Although low-wage workers pay little or no federal tax, they still pay high payroll and local taxes. To help such workers keep more of their earnings, refundable taxes like earned income tax credit and child refund taxes should be expanded, and sales taxes on food should be eliminated.

Social consequences of malnutrition.

Each year millions of people die from malnutrition-related problems. Those who survive are robbed of a healthy body, a sound intellect, and the hope for healthful living. Despite its global toll malnutrition is given limited attention by the world community; hence, it is generally viewed as a silent emergency by advocacy organizations. The causes and consequences of malnutrition are complex, and it will require the concerted efforts of all social institutions, including the social work profession, to combat malnutrition effectively. This article examines social determinants and consequences of malnutrition and suggests several social work actions that might be helpful toward minimizing malnutrition.

Activity of pleconaril against enteroviruses.

The activity of pleconaril in cell culture against prototypic enterovirus strains and 215 clinical isolates of the most commonly isolated enterovirus serotypes was examined. The latter viruses were isolated by the Centers for Disease Control and Prevention during the 1970s and 1980s from clinically ill subjects. Pleconaril at a concentration of

Health for all: is there health parity between blacks and whites?

Although various health care policies and health-promoting efforts by individuals have created a climate for healthy living, minorities still face higher health risks than Whites; this is especially true for Black Americans. The latest data show Blacks are especially vulnerable to a variety of preventable diseases and premature deaths. The findings show that they are better off than Whites on only two out of 18 health indicators examined. This paper presents several strategies to promote healthier living for Black Americans.

Promoting maternal health in developing countries.

Most maternal deaths are preventable, yet more than 500,000 women die annually worldwide. However, the risk of maternal mortality is unevenly distributed; 99 percent of all maternal deaths occur in developing countries. This article examines the causes of this disparity and suggests several recommendations for social workers to promote maternal health in developing countries.

Health care strategies for Asian American patients.

The health status of Asian Americans is at risk because the existing health care delivery system is unable to provide ethnic-sensitive health care services. This condition is attributed to the changing policies and practices of the health care system of the past decades. Thus it is argued that health care providers must become more knowledgeable about the specific health needs of Asian Americans.

Hypothermia as a threat to the elderly.

Because of high fuel costs and the aging of the population, more people than ever before in the United States are potential victims of accidental hypothermia. By mounting public awareness campaigns and other coordinated efforts, social workers and other concerned groups can do much to avert preventable deaths among the elderly from this public health threat.