Failure of dideoxynucleosides to inhibit human immunodeficiency virus replication in cultured human macrophages.

Primary human monocyte-derived macrophages (MDM) were shown to have diminished deoxynucleoside kinase activities compared to T lymphoblasts, and a reduced ability to phosphorylate dideoxynucleosides with anti-human immunodeficiency virus (HIV) activity. These drugs, azidothymidine (AZT), dideoxycytidine (ddC), and dideoxyadenosine (ddA), which are potent anti-HIV agents in CD4 lymphocytes, did not inhibit HIV replication in MDM, even at concentrations of 100 microM. This drug concentration of AZT is approximately 100-fold higher than the levels attained in the serum of treated patients and the levels required to inhibit HIV replication in lymphocytes. These observations may explain the failure of AZT therapy to clear viremia, consistent with the presence of a drug-resistant reservoir of infected cells in vivo. New therapeutic approaches to inhibit the replication of HIV in MDM may be needed

Aspects of mathematical programming in financial corporate planning

Imperial Users onl

Tracking bacterial pollution in the Cains Brook/Mill Creek watershed: Implications for policy and management

Pathogenic fecal bacteria present a management challenge when they contaminate surface waters used by humans. This study examined the extent to which the ongoing Cains Brook/Mill Creek watershed restoration in Seabrook, NH has successfully characterized the problem of bacterial pollution and implemented mitigation practices. Guided by the policy sciences analytical framework, this study employed a policy implementation audit reviewing relevant bacteria source tracking data, interviews and online surveys as a means to triangulate multiple data sources. Results indicate that bacteria arise from multiple sources and impairments still exist, although bacteria levels were not generally high. Management activities have likely reduced some sources, especially human-borne bacteria, but not others, and there are a variety of misperceptions regarding sources and mitigation techniques. Recommendations for future actions include enhancing bacterial source monitoring and modeling, using a larger-scale watershed-based approach to enhance cooperative efforts and increasing outreach to dispel misperceptions

Apoptosis in Drosophila: neither fish nor fowl (nor man, nor worm).

Studies in a wide variety of organisms have produced a general model for the induction of apoptosis in which multiple signaling pathways lead ultimately to activation of the caspase family of proteases. Once activated, these enzymes cleave key cellular substrates to promote the orderly dismantling of dying cells. A broad similarity exists in the cell death pathways operating in different organisms and there is a clear evolutionary conservation of apoptotic regulators such as caspases, Bcl-2 family members, inhibitor of apoptosis (IAP) proteins, IAP antagonists and caspase activators. Despite this, studies in Caenorhabditis elegans, Drosophila and vertebrates have revealed some apparent differences both in the way apoptosis is regulated and in the way individual molecules contribute to the propagation of the death signal. For example, whereas cytochrome c released from mitochondria clearly promotes caspase activation in vertebrates, there is no documented role for cytochrome c in C. elegans apoptosis and its role in Drosophila is highly controversial. In addition, the apoptotic potency of IAP antagonists appears to be greater in Drosophila than in vertebrates, indicating that IAPs may be of different relative importance in different organisms. Thus, although Drosophila, worms and humans share a host of apoptotic regulators, the way in which they function may not be identical

Network Overload due to Massive Attacks

We study the cascading failure of networks due to overload, using the betweenness centrality of a node as the measure of its load following the Motter and Lai model. We study the fraction of survived nodes at the end of the cascade $p_f$ as function of the strength of the initial attack, measured by the fraction of nodes $p$, which survive the initial attack for different values of tolerance $\alpha$ in random regular and Erd\"os-Renyi graphs. We find the existence of first order phase transition line $p_t(\alpha)$ on a $p-\alpha$ plane, such that if $p <p_t$ the cascade of failures lead to a very small fraction of survived nodes $p_f$ and the giant component of the network disappears, while for $p>p_t$, $p_f$ is large and the giant component of the network is still present. Exactly at $p_t$ the function $p_f(p)$ undergoes a first order discontinuity. We find that the line $p_t(\alpha)$ ends at critical point $(p_c,\alpha_c)$ ,in which the cascading failures are replaced by a second order percolation transition. We analytically find the average betweenness of nodes with different degrees before and after the initial attack, investigate their roles in the cascading failures, and find a lower bound for $p_t(\alpha)$. We also study the difference between a localized and random attacks

Filling a GAP(DH) in Caspase-Independent Cell Death

Mitochondrial outer-membrane permeabilization can lead to cell death even without activation of caspases. In this issue of Cell, Colell et al. (2007) identify the glycolytic enzyme glyceraldehyde-3-phosphate dehydrogenase as a potent inhibitor of caspase-independent cell death that may allow metabolically active cells to survive mitochondrial insult